Reaction mass of m-cresol and 2-chloro-m-cresol and 6-chloro-m-cresol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.32 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

82.9 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route specific dose descriptor is not available.

AF for dose response relationship:

1

Justification:

NOAEL was chosen

AF for differences in duration of exposure:

2

Justification:

According to ECHA guidance document R8

AF for interspecies differences (allometric scaling):

1

Justification:

Not required according to ECHA guidance document R8

AF for other interspecies differences:

2.5

Justification:

According to ECHA guidance document R8

AF for intraspecies differences:

5

Justification:

According to ECHA guidance document R8

AF for the quality of the whole database:

1

Justification:

database is reliable and of high quality

AF for remaining uncertainties:

1

Justification:

Not necessary

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

DNEL related information

DNEL derivation method:

other: VCI concept for corrosive substances

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.47 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

Value:

47 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL of the 2 generation study resulted in the lowest DNEL

AF for dose response relationship:

1

Justification:

NOAEL was chosen

AF for differences in duration of exposure:

2

Justification:

According to ECHA guidance document R8

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA guidance document R8

AF for other interspecies differences:

2.5

Justification:

According to ECHA guidance document R8

AF for intraspecies differences:

5

Justification:

According to ECHA guidance document R8

AF for the quality of the whole database:

1

Justification:

database is reliable and of high quality

AF for remaining uncertainties:

1

Justification:

not necessary

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

No repeated dose toxicity study with Preventol KMX is available. However a read across to 4-chloro-3-methylphenol was shown to be scientifically reliable. A detailed justification for the read-across is provided in the technical dossier (see IUCLID Section 13) as well as in the Summary of Toxicokinetics, metabolism and distribution in IUCLID section 7.1).

Conversion of oral NOAEL to inhalatory NAEC

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to-route extrapolation based on the ECHA guidance document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012.

The lowest NOAEL within a repeated dose study was achieved within a 2-generation oral feeding toxicity study performed on 4-chloro-3-methylphenol (Eiben, 2006). Systemic toxicity was observed in parental animals of the F0 and the F1 generation at 12000 and 3000 ppm, respectively. No effects on pups at dose levels of no or moderate maternal toxicity were evident. Nevertheless, conversion of the lowest dose level at which no adverse effect was observed using the body weight and food intake values resulted in the lowest NOAEL within all available repeated dose studies.Therefore, this NOAEL of 47 mg/kg bw/d was used as starting point to derive worker DNELs.

The conversion of an oral NOAEL into an inhalatory NAEC is performed using the following equation:

 

Corrected inhalatory NAEC = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x sRVhuman/wRV

                                                = oral NOAEL 47 mg/kg bw/d x 1/0.38m³/kg bw x 1 x 6.7 m³/10 m³

sRV: standard respiratory volume, ABS: absorption, wRV: worker respiratory volume

Thus, the corrected starting point for inhalation route was 47 x 6.7 / (10 x 0.38) = 82.9 mg/m³

Systemic DNEL derivation using the inhalatory NAEC

In the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. However, this factor is considered not relevant as toxicokinetic data on 4-chloro-3-methylphenol indicate an almost complete absorption of Preventol KMX after oral application. Factors for exposure duration (2), interspecies differences (2.5) and intraspecies differences (5) were applied according to ECHA Guidance document R8.

Thus, the long-term inhalation systemic DNEL is calculated to be 3.32 mg/m³.

Derivation of long-term inhalation local DNEL

Another approach to derive DNELs for substances whose primary effect on human health is irritation/corrosion was suggested by VCI (Verband der Chemischen Industrie e.V., 2010). A toxicological Task Force within the German VCI discussed the derivation of DNEL for local irritating compounds with a limited database. The experts developed upper boundary values for irritating and/or corrosive compounds based on available data. In particular the expert Task Force evaluated the German MAK-values published in the TRGS900 in 2009. For irritating compounds labelled with R36 or R38 but without relevant inhalation toxicity data available, the TF developed a generic upper boundary value of 10 mg/m3; for compounds with corrosive properties (R34 or R35) a respective value of 1 mg/m3 is developed.

Based on this approach the inhalation DNEL for long-term local effects is set to 1 mg/m3.

Conversion of oral NOAEL to dermal NAEL

The lowest NOAEL within a repeated dose study was achieved within a 2-generation oral feeding toxicity study performed on 4-chloro-3-methylphenol (Eiben, 2006). Systemic toxicity was observed in parental animals of the F0 and the F1 generation at 12000 and 3000 ppm, respectively. No effects on pups at dose levels of no or moderate maternal toxicity were evident. Nevertheless, conversion of the lowest dose level at which no adverse effect was observed using the body weight and food intake values, resulted in the lowest NOAEL within all available repeated dose studies.Therefore, this NOAEL of 47 mg/kg bw/d was used as starting point to derive worker DNELs.

For calculating the systemic dermal DNEL for workers no absorption difference between rat and human skin was assumed. No factor for time extrapolation was used as the substance was administered 5 days/week. For the dermal long-term systemic worker DNEL the following AFs were applied according to ECHA Guidance document R8: inter species factor 2.5, allometric scaling factor 4, intra species factor 5, exposure duration factor 2; => overall AF= 100

Thus, the long-term systemic dermal DNEL for workers is 0.47 mg/kg bw/d.

As no hazard could be evidenced in the acute toxicity studies in a worst-case assumption the systemic short-term exposure is covered by the long-term systemic DNEL. However, due to its corrosive and skin sensitizing properties the substance was allocated to the medium hazard band.

Short-term local DNELs

Preventol KMX showed corrosive properties in an in vitro skin corrosion assay. Further data on sensitization indicate a medium hazard of Preventol KMX. Local effects will therefore be addressed via qualitative risk assessment and no DNELs for local effects are derived. The oral route is not relevant for workers. In addition it is assumed that only workers will come in contact with the neat substances

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.82 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Value:

40.9 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route specific dose descriptor is not available.

AF for dose response relationship:

1

Justification:

NOAEL was chosen

AF for differences in duration of exposure:

2

Justification:

According to ECHA guidance document R8

AF for interspecies differences (allometric scaling):

1

Justification:

According to ECHA guidance document R8

AF for other interspecies differences:

2.5

Justification:

According to ECHA guidance document R8

AF for intraspecies differences:

10

Justification:

According to ECHA guidance document R8

AF for the quality of the whole database:

1

Justification:

database is reliable and of high quality

AF for remaining uncertainties:

1

Justification:

not necessary

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.24 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

Value:

47 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL of the 2 generation study resulted in the lowest DNEL

AF for dose response relationship:

1

Justification:

NOAEL was chosen

AF for differences in duration of exposure:

2

Justification:

According to ECHA guidance document R8

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA guidance document R8

AF for other interspecies differences:

2.5

Justification:

According to ECHA guidance document R8

AF for intraspecies differences:

10

Justification:

According to ECHA guidance document R8

AF for the quality of the whole database:

1

Justification:

database is reliable and of high quality

AF for remaining uncertainties:

1

Justification:

not necessary

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.24 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

Value:

47 mg/kg bw/day

AF for dose response relationship:

1

Justification:

NOAEL was chosen

AF for differences in duration of exposure:

2

Justification:

According to ECHA guidance document R8

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA guidance document R8

AF for other interspecies differences:

2.5

Justification:

According to ECHA guidance document R8

AF for intraspecies differences:

10

Justification:

According to ECHA guidance document R8

AF for the quality of the whole database:

1

Justification:

database is reliable and of high quality

AF for remaining uncertainties:

1

Justification:

not necessary

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Preventol KMX is used as an odour agent in cleaning products. After initial industrial manufacturing (i.e. mixing of the ingredients) the concentration of Preventol KMX in the disinfectant concentrate (sales product) is 0.3 to 0.5%. The general population may therefore come into contact with Preventol KMX at concentrations of 0.3 to 0.5% by the use of the disinfectant concentrate. The ready to use mixture of the disinfectant is obtained after 20 fold dilution of the disinfectant concentrate with water and contains thereafter 0.015 to 0.025% Preventol KMX. Taken into account the dilution of Preventol KMX corrosion and irritation after skin contact or upon inhalation is not expected. Therefore no DNELs for local effects are assessed.However, due to its corrosive and skin sensitizing properties the substance was allocated to the medium hazard band.

No repeated dose toxicity study with Preventol KMX is available. However a read across to 4-chloro-3-methylphenol was shown to be scientifically reliable. A detailed justification for the read-across is provided in the technical dossier (see IUCLID Section 13) as well as in the Summary of Toxicokinetics, metabolism and distribution in IUCLID section 7.1).

Conversion of oral NOAEL to inhalatory NAEC

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to-route extrapolation based on the ECHA guidance document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012.

The lowest NOAEL within a repeated dose study was achieved within a 2-generation oral feeding toxicity study performed on 4-chloro-3-methylphenol (Eiben, 2006). Systemic toxicity was observed in parental animals of the F0 and the F1 generation at 12000 and 3000 ppm, respectively. No effects on pups at dose levels of no or moderate maternal toxicity were evident. Nevertheless, conversion of the lowest dose level at which no adverse effect was observed, using the body weight and food intake values, resulted in the lowest NOAEL within all available repeated dose studies.Therefore, this NOAEL of 47 mg/kg bw/d was used as starting point to derive worker DNELs.

The conversion of an oral NOAEL into an inhalatory NAEC is performed using the following equations:

Corrected inhalatory NAEC = oral NOAEL x 1/sRVrat x ABSoral-rat/ABSinh-human

                                             = oral NOAELmg/kg bw/dx 1/1.15 m³/kg bw x 1

 

sRV: standard respiratory volume, ABS: absorption

Thus, the corrected starting point for inhalation route was 47 x 1 / 1.15 = 40.9 mg/m³

Systemic DNEL derivation using the inhalatory NAEC

In the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. However, this factor is considered not relevant as toxicokinetic data on 4-chloro-3-methylphenol indicate an almost complete absorption of Preventol KMX after oral application. Factors for exposure duration (2), interspecies differences (2.5) and intraspecies differences (10) were applied according to ECHA Guidance document R8.

Thus, the long-term inhalation systemic DNEL is calculated to be 0.82 mg/m³.

Conversion of oral NOAEL to dermal NAEL

The lowest NOAEL within a repeated dose study was achieved within a 2-generation oral feeding toxicity study performed on 4-chloro-3-methylphenol (Eiben, 2006). Systemic toxicity was observed in parental animals of the F0 and the F1 generation at 12000 and 3000 ppm, respectively. No effects on pups at dose levels of no or moderate maternal toxicity were evident. Nevertheless, conversion of the lowest dose level at which no adverse effect was observed, using the body weight and food intake values, resulted in the lowest NOAEL within all available repeated dose studies.Therefore, this NOAEL of 47 mg/kg bw/d was used as starting point to derive worker DNELs.

For calculating the systemic dermal DNEL for the general population no absorption difference was assumed. For the dermal long-term systemic DNEL the following AFs were applied according to ECHA Guidance document R8:

inter species factor 2.5, allometric scaling factor 4, intra species factor 10, exposure duration factor 2 => overall AF= 200

Thus, the long-term systemic dermal DNEL for the general population is 0.24 mg/kg bw/d.

For the oral long-term systemic DNEL the following AFs were applied:

inter species factor 2.5, allometric scaling factor 4, intra species factor 10, exposure duration factor 2; => overall AF = 200

Thus, the long-term systemic oral DNEL for general population is 0.24 mg/kg bw/d.

Short-term local DNELs

The consumer will not get into contact with undiluted Preventol KMX. Therefore no DNELs for local effects are assessed.