Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA)
AF for interspecies differences (allometric scaling):
4
Justification:
Default value (ECHA)
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA)
AF for intraspecies differences:
5
Justification:
Default value (ECHA) for workers
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

p-Cresol (CAS No. 106-44-5)

DNELs worker

INTRODUCTION

Local effects:

Para-cresol has corrosive properties. Under R67/548/EEC (29. ATP) p-cresol is classified as corrosive: R 34 = causes burns. According to Regulation (EC) No. 1272/2008 the substance is allocated to Category 1B of skin corrosive substances; Hazard Communication H314.

Due to the corrosive properties of p-cresol it is not appropriate to conduct a route-to-route extrapolation for local effects. The available data for p-cresol in animals are not sufficiently robust to derive a clear threshold value and to calculate a DNEL for local effects at the respiratory tract. Based on the available data a qualitative risk assessment approach will be followed as outlined in the REACH “Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health” (Version 2.1), November 2012. Due to the corrosive properties of p-cresol (R34) it will be allocated to the moderate hazard category.

Systemic effects:

Comprehensive and reliable studies are available after oral dosing to define reliable starting-points and to derive DNEL values for systemic toxicity. Route-to-route extrapolation can be conducted for systemic effects because p-cresol is absorbed across the respiratory and gastrointestinal tract and through the intact skin.

Overall; due to the corrosive properties of p-cresol (R34) it will be allocated to the moderate hazard category.

WORKER

SYSTEMIC EFFECTS

There is no Occupational Exposure Level (OEL) for the cresols available (Greim 2000, SCOEL2002) which could be used as DNEL and/or to estimate the risk for humans.

SCOEL 2002 (SCOEL/SUM/96 final March 2002): “The systemic toxicity of the cresol isomers has been adequately studied in oral animal experiments, resulting in a NOAEL for rats of 50 mg/kg bw/day. However, hazard assessment based on oral studies is not appropriate because there are indications that local irritation is the critical effect of cresol vapours. Adequate inhalation studies are not available…. 8 hour TWA : no recommendation made”

DNEL (Short term)

Under R67/548/EEC (29. ATP) p-cresol is classified as T; R24/25-34 (C>=5%); toxic in contact with skin and if swallowed – causes burns.

A DNEL (short term) should be derived if any acute toxicity hazard has been identified and there is a potential for high peak exposure. High peak exposures are usually for the inhalation route. This takes into consideration local and systemic toxicity. There are no valid LC50 values or No Adverse Effect Concentrations (NOAEC) values for p-cresol available which could be used to set a DNEL (short term). In such a case a DNEL for systemic short term toxicity can be derived by applying an exceeding factor of 2 to the long term DNEL.

DNEL (short term, systemic, dermal) : 1.00 mg/kg bw.

DNEL (acute, systemic, inhalation): 7 mg/m³.

Remark: these DNELs do not take into consideration local toxicity.

DNEL (long-term)

Choice of the starting point

There are no long-term studies (>12 months) available for the individual isomer p-cresol, but there are long-term toxicity and carcinogenicity studies with rats and mice available using a mixture of m-and p-cresol which could be considered instead (US Department for Health and Human Services 2007). However, from each species only one gender is introduced in the study. Furthermore, clinical chemistry, blood biochemistry and haematology are not performed and the reported toxicity findings are limited to histopathological changes. Thus, the toxicological picture caused by m-/p-cresol mixture might be incomplete. In addition, the guideline requirements for long-term toxicity studies are not fulfilled. Therefore these studies were not taken into account for non-carcinogenicity endpoints.

There are two studies using similar treatment times and the same application routes. Repeated oral dosing for 13 weeks by gavage resulted in a NOAEL of 50 mg/kg bw/day and a LOAEL of 175 mg/kg bw/day. In a 2-generation reproductive toxicity study (accounting for a treatment time of 19 weeks) the NOAEL (general toxicity) is 30 mg/kg bw/day and LOAEL is 175 mg/kg bw/day. Considering the NOAELs and LOAELs for both studies it has to be noted that the spacing between NOAELs and LOAELs of the respective studies are greater in the 2-generation studies than in the respective repeated dose toxicity studies. Therefore the NOAEL from the 13 week gavage study are used for the following calculations.

DNEL (long-term, systemic, oral exposure)

The NOAEL (subchronic, oral) is 50 mg/kg bw/day

The following factors have to be considered (default factors as defined in the guidance document):

• Exposure duration subchronic to chronic 2

• Interspecies factor: 4

• Remaining differences 2.5;

• Intraspecies: 5 (Workers)

=> overall assessment factor: 100

Based on a NOAEL of 50 mg/kg bw/d and an overall assessment factor or 100 the DNEL (oral, long term systemic; workers) for p-cresol is 0.5 mg/ kg bw.

DNEL (long term, systemic, dermal exposure)

Route-to-route extrapolation can be conducted for systemic effects because p-cresol is absorbed across the respiratory and gastrointestinal tract and through the intact skin. According to the Guidance on information requirements and chemical safety assessment, Chapter R8 no additional assessment factor is necessary for oral to dermal extrapolation. Consequently the DNEL (dermal long term, systemic, worker) is equal to the oral DNEL = 0.5 mg/kg bw/day.

DNEL (long-term, systemic, inhalation exposure)

According of the recent published Guidance Document (Chapter R8) an assessment factor has to be considered for oral to inhalation extrapolation. In contrast to that default assumption, as it is well known that p-cresol is well absorbed after oral, dermal and inhalation exposure, in this case no additional assessment factor has to be used.

Based on a body weight for worker of 70 kg and a respiratory volume (light activity) for workers 8 h exposure of 10 m³/person the calculated DNEL (long-term, systemic; inhalation exposure) is 3.5 mg/m³.

Remark: the DNEL does not take into consideration local toxicity at the respiratory tract

LOCAL EFFECTS

The most prominent toxic effects of p-cresol are the local highly irritating or even caustic property of p-cresol to skin and mucous membranes and the respiratory tract. However, there are no valid dermal or inhalation long-term exposure data available to derive dose-response information with respect to irritation or corrosion. In addition, as the limited acute toxicity studies using inhalational or dermal exposure route did not grade the observed irritation effects, they also do not provide a basis for a setting a DNEL. Thus, a threshold cannot be given and a DNEL for local toxicity after dermal or inhalation exposure cannot be derived.

Due to the corrosive properties of p-cresol it is not appropriate to conduct a route-to-route extrapolation for local effects.

In such a case, when derivation of a DNEL is not possible the REACH Guidance on information requirements and chemical safety assessment indicates that qualitative data would usually lead to a more qualitative approach to assess and to control these risks and refers to Part E (Risk characterization, Version 2.0, November 2012), Chapter 3.4 (Conduct qualitative risk characterization): “For irritation and corrosion, usually the available in vitro and in vivo studies tend to provide only qualitative (yes or no) or semi-quantitative/potency information (for example corrosive after 3 minutes or 4 hour exposure: higher or lower scores for erythema, edema and other irritating effects”. Further on it is stated. "Substances with the R-phrases R34 (causes burns), R41 (risk of serious damage to the eyes) or R36/37/38 (irritating to eyes, respiratory tract and skin) which relate to corrosive or severe irritant effects to the eye or irritant effects to the eyes, respiratory tract and skin simultaneously, are allocated to the moderate hazard category on the basis that exposure to such corrosives, eye damaging or irritant substances should be well controlled".

The approach outlined in the REACH guidance Part E will be followed for p-cresol. A systemic DNEL will be derived and due to the corrosive properties of p-cresol on skin and eye (R34) it will be allocated to the moderate hazard category concerning the local effects.

As outlined and discussed in the respective sections "Human information" long-term occupational medical investigations (1997-2011) with cresols are available (Leng 2012). Comprehensive medical investigations performed with workers from 2 productions plants manufacturing o-, m- and p-cresol are documented and discussed. Each site handles, produces or processes several thousand tonnes cresols per year. In the same period during routine handling when no respiratory protection devices were used, exposure levels have been measured by air monitoring (Allmendinger 2012) showing that concentrations were up to 0.91 mg/m³ (8h-time-weighed average) and 1.87 mg/m³ (15 min peak exposure). Occupational medical surveillance data from about 100 workers per year over a period of 15 years (1997-2011) have been evaluated and did not reveal any health effects like irritations of the skin, mucosa membranes or upper respiratory tract which could be attributed to cresol exposure during routine handling at the workplace when no respiratory protection devices were used. Thus, the follow-up period is sufficiently long to exclude even delayed adverse local effects in humans and it can be concluded that no effects are observed up to 0.91 mg/m³ (8h-time-weighed average) and 1.87 mg/m³ (15 min peak exposure).

Generic cut-off values for local respiratory tract irritation by irritating or corrosive substances were developed by the Working Group of the Chemical Industry Association VCI (Messinger H, Regulatory Toxicology and Pharmacology 68 (2014) 317-324). Existing occupational exposure limits (OEL) as surrogate for cut-off limits representing safe exposure under working conditions were grouped under certain criteria for substances that are legally classified in Europe as irritating or corrosive. As a result, it was demonstrated that the OEL for irritating substances is not lower than 10 mg/m³ and for corrosives not lower than 1 mg/m³.

In the light of this general evaluation it is plausible that no health effects were reported for cresols at concentrations up to 0.91 mg/m³ (8h-time-weighed average) and 1.87 mg/m³ (15 min peak exposure) in the occupational setting over a period of 15 years.

In conclusion, for local respiratory tract irritation/corrosion no dose-response or threshold value is available to calculate a full DNEL and, consequently, a qualitative risk assessment approach is necessary for local effects. p-Cresol is allocated in the moderate hazard band. Taking into account the available human occupational data for and comparison with thresholds for other corrosive compounds 0.9 mg/m³ is supported as (tentative) safe level for worker exposure (recommended operator exposure level).

DN(M)EL (Carcinogenicity)

There are no carcinogenicity bioassays or other chronic studies available to assess the carcinogenic potential of p-cresol, but there are long-term toxicity and carcinogenicity studies with rats and mice available using a mixture of m-and p-cresol which could be considered instead (US Department for Health and Human Services 2007) although from each species only one gender is introduced in the study. As discussed under 5.7 these 2-year studies did not reveal a clear carcinogenic potential (equivocal evidence in the rat based on renal adenomas at high doses and some evidence in the mouse based on forestomach squamous cell papillomas of minor significance for the human situation and assumed to be the result of chronic local irritation also at high doses).Based on these results and with respect to the available data on genotoxicity, carcinogenicity is covered by the DNEL for chronic toxicity.

DNEL Reproductive Toxicity

----Fertility

In 2-generation studies in rats according to the respective guideline with p-cresol, the NOAELs for fertility were determined to be 450 mg/kg bw/d, the highest dose in test. Since these NOAELs are much higher than the NOAELs for repeated dose toxicity, the long term DNEL (systemic, oral) covers the endpoint fertility.

----Developmental toxicity

In a developmental toxicity study in rats according to the respective guideline p-cresol induced slight fetotoxicity in the presence of maternal toxicity, thus leading to a NOAEL of 175 mg/kg bw/day. Since this NOAEL is much higher than the NOAEL for repeated dose toxicity, the long term DNEL (systemic, oral) covers the endpoint developmental toxicity.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.75 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA)
AF for interspecies differences (allometric scaling):
4
Justification:
Default value (ECHA)
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA)
AF for intraspecies differences:
10
Justification:
Default value (ECHA) for general population
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL extrapolated from long term DNEL

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:
0.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA)
AF for interspecies differences (allometric scaling):
4
Justification:
Default value (ECHA)
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA)
AF for intraspecies differences:
10
Justification:
Default value (ECHA) for general population
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

p-Cresol (CAS No. 106-44-5)

DNELs general population

INTRODUCTION

Local effects:

Para-cresol has corrosive properties. Under R67/548/EEC (29. ATP) p-cresol is classified as corrosive: R 34 = causes burns. According to Regulation (EC) No. 1272/2008 the substance is allocated to Category 1B of skin corrosive substances; Hazard Communication H314.

Due to the corrosive properties of p-cresol it is not appropriate to conduct a route-to-route extrapolation for local effects. The available data for p-cresol in animals are not sufficiently robust to derive a clear threshold value and to calculate a DNEL for local effects at the respiratory tract. Based on the available data a qualitative risk assessment approach will be followed as outlined in the REACH “Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health” (Version 2.1), November 2012. Due to the corrosive properties of p-cresol (R34) it will be allocated to the moderate hazard category.

Systemic effects:

Comprehensive and reliable studies are available after oral dosing to define reliable starting-points and to derive DNEL values for systemic toxicity. Route-to-route extrapolation can be conducted for systemic effects because p-cresol is absorbed across the respiratory and gastrointestinal tract and through the intact skin.

Overall; due to the corrosive properties of p-cresol (R34) it will be allocated to the moderate hazard category.

GENERAL POPULATION

SYSTEMIC EFFECTS

DNEL (Short term)

Under R67/548/EEC (29. ATP) p-cresol is classified as T; R24/25-34 (C>=5%); toxic in contact with skin and if swallowed – causes burns.

A DNEL (short term) should be derived if any acute toxicity hazard has been identified and there is a potential for high peak exposure. High peak exposures are usually for the inhalation route. This takes into consideration local and systemic toxicity. There are no valid LC50 values or No Adverse Effect Concentrations (NOAEC) values for p-cresol available which could be used to set a DNEL (short term).

In such a case a DNEL for systemic short term toxicity can be derived by applying an exceeding factor of 2 to the long term DNEL.

DNEL (short term, systemic, dermal): 0.5 mg/kg bw.

DNEL (acute, systemic, inhalation): 1.5 mg/m³.

Remark: these DNELs do not take into consideration local toxicity.

DNEL (long term)

Choice of the starting point

There are no long-term studies (>12 months) available for the individual isomer p-cresol, but there are long-term toxicity and carcinogenicity studies with rats and mice available using a mixture of m-and p-cresol which could be considered instead (US Department for Health and Human Services 2007). However, from each species only one gender is introduced in the study. Furthermore, clinical chemistry, blood biochemistry and haematology are not performed and the reported toxicity findings are limited to histopathological changes. Thus, the toxicological picture caused by m-/p-cresol mixture might be incomplete. In addition, the guideline requirements for long-term toxicity studies are not fulfilled. Therefore these studies were not taken into account for non-carcinogenicity endpoints.

There are two studies using similar treatment times and the same application routes. Repeated oral dosing for 13 weeks by gavage resulted in a NOAEL of 50 mg/kg bw/day and a LOAEL of 175 mg/kg bw/day. In a 2-generation reproductive toxicity study (accounting for a treatment time of 19 weeks) the NOAEL (general toxicity) is 30 mg/kg bw/day and LOAEL is 175 mg/kg bw/day. Considering the NOAELs and LOAELs for both studies it has to be noted that the spacing between NOAELs and LOAELs of the respective studies are greater in the 2-generation studies than in the respective repeated dose toxicity studies. Therefore the NOAEL from the 13 week gavage study are used for the following calculations.

DNEL (long-term, systemic, oral exposure)

The NOAEL (subchronic, oral) is 50 mg/kg bw/day

The following factors have to be considered (default factors as defined in the guidance document):

• Exposure duration subchronic to chronic 2

• Interspecies factor: 4

• Remaining differences 2.5;

• Intraspecies: 10 (General Public)

=> overall assessment factor: 200

Based on a NOAEL of 50 mg/kg bw/d and an overall assessment factor of 200 the DNEL (oral, long term systemic) for p-cresol is 0.25 mg/ kg bw(day.

DNEL (long-term, systemic, dermal exposure)

Route-to-route extrapolation can be conducted for systemic effects because p-cresol is absorbed across the respiratory and gastrointestinal tract and through the intact skin. According to the Guidance on information requirements and chemical safety assessment, Chapter R8 no additional assessment factor is necessary for oral to dermal extrapolation. Consequently the DNEL (dermal long term, systemic, worker) is equal to the oral DNEL = 0.25 mg/kg bw/day.

DNEL (long-term, systemic toxicity, inhalation exposure)

According of the recent published Guidance Document (Chapter R8) an assessment factor has to be considered for oral to inhalation extrapolation. In contrast to that default assumption, as it is well known that m-cresol and p-cresol are well absorbed after oral, dermal and inhalation exposure, in this case no additional assessment factor has to be used.

Based on a body weight for worker of 60 kg and a respiratory volume of 20 m³/person the calculated DNEL(long-term, systemic; inhalation exposure) is 0.75 mg/m³.

Remark: this DNEL does not take into consideration local toxicity of the respiratory tract.

LOCAL EFFECTS

The most prominent toxic effects of p-cresol are the local highly irritating or even caustic property of p-cresol to skin and mucous membranes and the respiratory tract. However, there are no valid dermal or inhalation long-term exposure data available to derive a dose-response information with respect to irritation or corrosion. In addition, as the limited acute toxicity studies using inhalational or dermal exposure route did not grade the observed irritation effects, they also do not provide a basis for a setting a DNEL. Thus, a threshold cannot be given and a DNEL for local toxicity after dermal or inhalation exposure cannot be derived.

In addition, it has to be taken into account that the general public is only be exposed to cresols in articles in which the cresol concentration does not exceed 0.1 %. The accepted fact that irritation/corrosion effects are concentration dependent, is considered by Directive 67/548/EEC as well as by the Regulation (EC) No.1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures. The defined threshold, below which no irritating properties are assumed for corrosive compounds in a mixture and consequently no classification is required, is given with 1 %. Therefore, based on the exposure of the general population to cresol containing articles at only very low concentrations, no corrosive or irritating effects are assumed. Thus, there is no need to derive DNELs for local effects for general public.

The following DNELs (general public) are not derived: DNEL (local, dermal, short term and long term); DNEL (local, inhalation, short term and long term). No hazard identified for concentrations of p-cresol below 1%.

DNEL (carcinogenicity)

There are no carcinogenicity bioassays or other chronic studies available to assess the carcinogenic potential of p-cresol, but there are long-term toxicity and carcinogenicity studies with rats and mice available using a mixture of m-and p-cresol which could be considered instead (US Department for Health and Human Services 2007) although from each species only one gender is introduced in the study.

As discussed under 5.7 these 2-year studies did not reveal a clear carcinogenic potential (equivocal evidence in the rat based on renal adenomas at high doses and some evidence in the mouse based on forestomach squamous cell papillomas of minor significance for the human situation and assumed to be the result of chronic local irritation also at high doses).Based on these results and with respect to the available data on genotoxicity, carcinogenicity is covered by the DNEL for chronic toxicity.

DNEL Reproductive Toxicity

----Fertility

In 2-generation studies in rats according to the respective guideline with p-cresol, the NOAELs for fertility was determined to be 450 mg/kg bw/d, the highest dose in test. Since these NOAELs are much higher than the NOAELs for repeated dose toxicity, the long term DNEL (systemic, oral) covers the endpoint fertility.

----Developmental toxicity

In a developmental toxicity study in rats according to the respective guideline p-cresol induced slight fetotoxicity in the presence of maternal toxicity, thus leading to a NOAEL of 175 mg/kg bw/day. Since this NOAEL is much higher than the NOAEL for repeated dose toxicity, the long term DNEL (systemic, oral) covers the endpoint developmental toxicity.