Dichloromethylbenzene

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Information/Assumptions regarding Toxicokinetics.

Type of information:

other: Information/Assumptions regarding Toxicokinetics.

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

accepted calculation method

Principles of method if other than guideline:

Information/Assumptions regarding Toxicokinetics.

GLP compliance:

no

Species:

other: Information/Assumptions regarding Toxicokinetics.

Strain:

other: Information/Assumptions regarding Toxicokinetics.

Details on test animals or test system and environmental conditions:

Information/Assumptions regarding Toxicokinetics.

Route of administration:

other: Information/Assumptions regarding Toxicokinetics.

Details on exposure:

Information/Assumptions regarding Toxicokinetics.

Duration and frequency of treatment / exposure:

Information/Assumptions regarding Toxicokinetics.

No. of animals per sex per dose / concentration:

Information/Assumptions regarding Toxicokinetics.

Positive control reference chemical:

Information/Assumptions regarding Toxicokinetics.

Details on study design:

Information/Assumptions regarding Toxicokinetics.

Details on dosing and sampling:

Information/Assumptions regarding Toxicokinetics.

Statistics:

Information/Assumptions regarding Toxicokinetics.

Metabolites identified:

no

Title: Information/Assumptions regarding Toxicokinetics:  

Dichloromethylbenzene (CAS no 29797-40-8) = Mixture of the isomers 2,4-dichlorotoluene, 2,5- dichlorotoluene, 3,4- dichlorotoluene, 2,3-dichlorotoluene and 2,6-dichlorotoluene

Author:

Dr. Harald Schlecker

Bayer AG

Research & Development, Pharmaceuticals

Industrial Chemicals Toxicology

42096 Wuppertal

Germany

Completion Date:

2020-03-02

Sponsor:

LANXESS Deutschland GmbH

51369 Leverkusen

Germany

There are no experimental toxicokinetic data available for Dichloromethylbenzene (CAS no 29797-40-8) and this statement is based on available data as physico-chemical data and toxicological data. This assumption was conducted based on the REACH ECHA “Guidance on information requirements and chemical safety assessment chapter R.7c” of the ECHA guidance document (Version 3.0, June 2017).

Available physico-chemical information taken into account:

Physical state:

Dichloromethylbenzene mixture is a light yellowish liquid organic substance with a solvent-like odour.

Structure:

Dichloromethylbenzene (CAS no 29797-40-8) = Mixture of the isomers 2,4-dichlorotoluene, 2,5- dichlorotoluene, 3,4- dichlorotoluene, 2,3-dichlorotoluene and 2,6-dichlorotoluene.

Molecular weight:

161.03 g/mol

Water solubility:

11.2 mg/L at 20 °C

Log Pow:

4.25 (calculated)

General considerations:

Absorption is a function of the potential for a substance to diffuse across biological membranes. In addition to molecular weight the most useful parameters providing information on this potential are the octanol/water partition coefficient (log P) value and the water solubility. The  log P value provides information on the relative solubility of the substance in water and the hydrophobic solvent octanol (used as a surrogate for lipid) and is a measure of lipophilicity.    Log P values above 0 indicate that the substance is more soluble in octanol than water i.e. lipophilic and negative values indicate that the substance is more soluble in water than octanol i.e. hydrophilic. In general, log P values between -1 and 4 are favourable for absorption. Nevertheless, a substance with such a log P value can be poorly soluble in lipids and hence not readily absorbed when its water solubility is very low. It is therefore important to consider both, the water solubility of a substance and its log P value, when assessing the potential of that substance to be absorbed.

In general, substances with a log P betweeen -1 and 4 are favourable regarding oral/GI absorption and respiratory absorption. Substance with a logP between1 and 4 favour dermal absorption. Moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed.

Due to the low molecular weight of 161.03 g/mol oral absorption is favoured. A molecular weight less than 100 favours dermal uptake. Above 500 the molecule may be too large.

No information of metabolic transformation of Dichloromethylbenze mixture is available.

Estimation of oral absorption:

In an acute oral toxicity study in male and female Wistar rats, the animals received the Dichloromethylbenze mixture via gavage. Following doses were tested: 1000, 2500, 2650 (only female rats), 3000, 3550, 5000 mg/kg bw. The LD 50 for male rats was 3179 mg/kg and the LD 50 for female rats was 2344 mg/kg bw.

In a subacute OECD Guideline 407 study (Repeated Dose 28-Day Oral Toxicity in Rodents), 5 male and 5 female Wistar-rats per group received 0, 20, 100 or 500 mg of the test substance daily per gavage on 7 days per week for 4 weeks. No substance-related deaths or symptoms were observed. Hematological and clinical-chemical parameter did not show any differences to the control animals. In male and female rats of the 500 mg/kg group a slight increase of liver weight and in male animals a slight hypertrophia of liver cells could be observed. In the epithelia of the kidney tubuli of male rats from 20 mg/kg upwards hyaline droplets were found; this was evaluated as an interaction with alpha-2-microglobulines, which is not relevant for humans. Initially at 500 mg/kg the distended tubuli of the kidney can be seen as a symptom of the early stage of a nephropathy. The NOAEL for male rats was therefore 100 mg/kg bw and for female rats the NOAEL was 500 mg/kg bw.

In a subchronic OECD Guideline 408 study (Repeated Dose 90-Day Oral Toxicity in Rodents), Wistar rats were treated with Dichloromethylbenzene for at least 90 consecutive days by daily. Among all the surviving animals treated with dichloromethylbenzene, the clinical observations revealed a dose dependent incidence of rales and /or hunched posture during the observation period. One female at 100 mg/kg/day showed signs of poor health at the end of the observation period.                                                                                                                                            

For all surviving animals in this study, no toxicologically significant changes were noted in functional observations, ophthalmoscopy, body weight, food consumption and haematology. During histopathological examination morphological changes were noted in kidney, liver, forestomach and thyroid.

Based on the adverse test item-related morphologic alterations in the kidneys of males at 400 mg/kg/day, a No Observed Adverse Effect Level (NOAEL) for Dichloromethylbenzene of 100

mg/kg/day was established for male rats.

For females, adverse test item-related alterations were only noted at 800 mg/kg/day as morphological changes in the liver. Based on these results a No Observed Adverse Effect Level (NOAEL) for Dichloromethylbenzene of 400 mg/kg/day could be considered for female animals.

Overall: Based on the water solubility of 11.2 mg/L absorption following ingestion seems limited. However, any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed. Molecular weights below 500 are favourable for absorption.

The acute oral toxicity of Dichloromethylbenze mixture is > 2000 mg/kg bw and the repeated dose toxicity is moderate (subacute: NOAEL for male rats was 100 mg/kg bw and for female rats the NOAEL was 500 mg/kg bw; subchronic: NOAEL for male rats was 100 mg/kg bw and for female rats the NOAEL was 800 mg/kg bw).

These data indicate a low to moderate bioavailability of Dichloromethylbenze mixture.

Estimation of dermal absorption:

An acute dermal toxicity study is available, but no repeated dose toxicity study.

In an acute dermal toxicity study in male and female Wistar rats the animals were treated with the test substance for 24 h on the shaved back and flank. The dose tested was 2000 mg/kg bw. After 24 h the occlusive coverage was removed and the leftovers of test substance were washed with lukewarm water. Up to 30 minutes after application the female and male animals made sounds. After one hour all animals were symptom-free. No local skin changes were observed. During the 14 day observation-period no animal died. The LD 50 therefore was >2000 mg/kg bw.

Overall: A substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/l, dermal uptake is likely to be low. A molecular Weight less than 100 favours dermal uptake. Above 500 the molecule may be too large. For substances with log P values Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high.

The acute dermal toxicity of Dichloromethylbenze mixture is > 2000 mg/kg bw.

These data indicate a low bioavailability of Dichloromethylbenze mixture.

Estimation of absorption via inhalation:

A not assignable acute inhalation toxicity study is available, but no repeated dose toxicity study.

In an acute inhalation study in male and female Wistar rats the test substance was vapoured dynamicly at temperatures of 20°C, 30°C and 95°C in a time-saturation-test. 200 l air/h where conveyed through 50g test substance. The results were following:

inhalation for 7 h (20°C): no mortality;                                                                                                  

inhalation for 7 h (30°C): no mortality;                                              

inhalation for 3 h (95°C): 2/10 (20 %) of the females died;                

inhalation for 7 h (95°C): 3/10 (30%) animals died. Intoxication symptoms: behaviour disturbance, difficulty of breathing, agitation sedation, irritation of the mucous membranes.

No LC50 was defined.

Overall: Moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed.

These data indicate a low to moderate bioavailability of Dichloromethylbenze mixture.

Estimation of distribution:

In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution. If the molecule is lipophilic (log P >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

Overall, for the absorbed amount of Dichloromethylbenze mixture a wide distribution in the body is assumed.

Estimation of accumulation:

Lipophilic substances have the potential to accumulate within the body. Substances with high    log P values tend to have longer half-lives unless their large volume of distribution is counter-balanced by a high clearance. On this basis, there is the potential for highly lipophilic substances (log P >4) to accumulate in individuals that are frequently exposed (e.g. daily at work) to that substance. Once exposure stops, the concentration within the body will decline at a rate determined by the half-life of the substance.

Dichloromethylbenze mixture has a log Pow of 4.25 (calculated).

Based on the log Pow an accumulation cannot be excluded. However, in the repeated dose toxicity studies no differences in the NOAELs in the subacute and subchronic studies were found. In the subacute repeated dose toxicity study a NOAEL for male rats of 100 mg/kg bw and for female rats the NOAEL of 500 mg/kg bw was found. In the subchronic study the NOAEL for male rats was 100 mg/kg bw and for female rats the NOAEL was 800 mg/kg bw.

Therefore, a low or no accumulation potential is assumed.

Estimation of metabolism:

In vitro and in vivo genotoxicity data of Dichloromethylbenze mixture do not indicate any genotoxic metabolites.

The substance is negative in the absence and in the presence of S9 extracts (Ames test (Bacterial Reverse Mutation Assay) and the HPRT test (In Vitro Mammalian Cell Gene Mutation Test)).

The in vivo MNT (Mammalian Erythrocyte Micronucleus Test) was also negative.

Estimation of excretion:

Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility and ionization of the molecule at the pH of urine.

Substances that are excreted in the bile tend to have higher molecular weights or may be conjugated as glucuronides or glutathione derivatives. Substances in the bile pass through the intestines before they are excreted in the faeces and as a result may undergo enterohepatic recycling.

Other substances excreted in the faeces are those that have diffused out of the systemic circulation into the gastrointestinal tract directly, substances which have been removed from the gastrointestinal mucosa by efflux mechanisms and non-absorbed substances that have been ingested or inhaled and subsequently swallowed.

The characteristics for a favourable urinary excretion are not fulfilled. Based on the low water solubility of 11.2 mg/L and an expected low bioavailability an excretion mainly via faeces is assumed.

---------------------------------------                                   

Dr. Harald Schlecker

Bayer AG

Research & Development, Pharmaceuticals

Industrial Chemicals Toxicology

Executive summary:

Title: Information/Assumptions regarding Toxicokinetics:  

Dichloromethylbenzene (CAS no 29797-40-8) = Mixture of the isomers 2,4-dichlorotoluene, 2,5- dichlorotoluene, 3,4- dichlorotoluene, 2,3-dichlorotoluene and 2,6-dichlorotoluene

Author:

Dr. Harald Schlecker

Bayer AG

Research & Development, Pharmaceuticals

Industrial Chemicals Toxicology

42096 Wuppertal

Germany

Completion Date:

2020-03-02

Sponsor:

LANXESS Deutschland GmbH

51369 Leverkusen

Germany

There are no experimental toxicokinetic data available for Dichloromethylbenzene (CAS no 29797-40-8) and this statement is based on available data as physico-chemical data and toxicological data. This assumption was conducted based on the REACH ECHA “Guidance on information requirements and chemical safety assessment chapter R.7c” of the ECHA guidance document (Version 3.0, June 2017).

Available physico-chemical information taken into account:

Physical state:

Dichloromethylbenzene mixture is a light yellowish liquid organic substance with a solvent-like odour.

Structure:

Dichloromethylbenzene (CAS no 29797-40-8) = Mixture of the isomers 2,4-dichlorotoluene, 2,5- dichlorotoluene, 3,4- dichlorotoluene, 2,3-dichlorotoluene and 2,6-dichlorotoluene.

Molecular weight:

161.03 g/mol

Water solubility:

11.2 mg/L at 20 °C

Log Pow:

4.25 (calculated)

General considerations:

Absorption is a function of the potential for a substance to diffuse across biological membranes. In addition to molecular weight the most useful parameters providing information on this potential are the octanol/water partition coefficient (log P) value and the water solubility. The  log P value provides information on the relative solubility of the substance in water and the hydrophobic solvent octanol (used as a surrogate for lipid) and is a measure of lipophilicity.    Log P values above 0 indicate that the substance is more soluble in octanol than water i.e. lipophilic and negative values indicate that the substance is more soluble in water than octanol i.e. hydrophilic. In general, log P values between -1 and 4 are favourable for absorption. Nevertheless, a substance with such a log P value can be poorly soluble in lipids and hence not readily absorbed when its water solubility is very low. It is therefore important to consider both, the water solubility of a substance and its log P value, when assessing the potential of that substance to be absorbed.

In general, substances with a log P betweeen -1 and 4 are favourable regarding oral/GI absorption and respiratory absorption. Substance with a logP between1 and 4 favour dermal absorption. Moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed.

Due to the low molecular weight of 161.03 g/mol oral absorption is favoured. A molecular weight less than 100 favours dermal uptake. Above 500 the molecule may be too large.

No information of metabolic transformation of Dichloromethylbenze mixture is available.

Estimation of oral absorption:

In an acute oral toxicity study in male and female Wistar rats, the animals received the Dichloromethylbenze mixture via gavage. Following doses were tested: 1000, 2500, 2650 (only female rats), 3000, 3550, 5000 mg/kg bw. The LD 50 for male rats was 3179 mg/kg and the LD 50 for female rats was 2344 mg/kg bw.

In a subacute OECD Guideline 407 study (Repeated Dose 28-Day Oral Toxicity in Rodents), 5 male and 5 female Wistar-rats per group received 0, 20, 100 or 500 mg of the test substance daily per gavage on 7 days per week for 4 weeks. No substance-related deaths or symptoms were observed. Hematological and clinical-chemical parameter did not show any differences to the control animals. In male and female rats of the 500 mg/kg group a slight increase of liver weight and in male animals a slight hypertrophia of liver cells could be observed. In the epithelia of the kidney tubuli of male rats from 20 mg/kg upwards hyaline droplets were found; this was evaluated as an interaction with alpha-2-microglobulines, which is not relevant for humans. Initially at 500 mg/kg the distended tubuli of the kidney can be seen as a symptom of the early stage of a nephropathy. The NOAEL for male rats was therefore 100 mg/kg bw and for female rats the NOAEL was 500 mg/kg bw.

In a subchronic OECD Guideline 408 study (Repeated Dose 90-Day Oral Toxicity in Rodents), Wistar rats were treated with Dichloromethylbenzene for at least 90 consecutive days by daily. Among all the surviving animals treated with dichloromethylbenzene, the clinical observations revealed a dose dependent incidence of rales and /or hunched posture during the observation period. One female at 100 mg/kg/day showed signs of poor health at the end of the observation period.                                                                                                                                            

For all surviving animals in this study, no toxicologically significant changes were noted in functional observations, ophthalmoscopy, body weight, food consumption and haematology. During histopathological examination morphological changes were noted in kidney, liver, forestomach and thyroid.

Based on the adverse test item-related morphologic alterations in the kidneys of males at 400 mg/kg/day, a No Observed Adverse Effect Level (NOAEL) for Dichloromethylbenzene of 100

mg/kg/day was established for male rats.

For females, adverse test item-related alterations were only noted at 800 mg/kg/day as morphological changes in the liver. Based on these results a No Observed Adverse Effect Level (NOAEL) for Dichloromethylbenzene of 400 mg/kg/day could be considered for female animals.

Overall:Based on the water solubility of 11.2 mg/L absorption following ingestion seems limited. However, any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed. Molecular weights below 500 are favourable for absorption.

The acute oral toxicity of Dichloromethylbenze mixture is > 2000 mg/kg bw and the repeated dose toxicity is moderate (subacute: NOAEL for male rats was 100 mg/kg bw and for female rats the NOAEL was 500 mg/kg bw; subchronic: NOAEL for male rats was 100 mg/kg bw and for female rats the NOAEL was 800 mg/kg bw).

These data indicate a low to moderate bioavailability of Dichloromethylbenze mixture.

Estimation of dermal absorption:

An acute dermal toxicity study is available, but no repeated dose toxicity study.

In an acute dermal toxicity study in male and female Wistar rats the animals were treated with the test substance for 24 h on the shaved back and flank. The dose tested was 2000 mg/kg bw. After 24 h the occlusive coverage was removed and the leftovers of test substance were washed with lukewarm water. Up to 30 minutes after application the female and male animals made sounds. After one hour all animals were symptom-free. No local skin changes were observed. During the 14 day observation-period no animal died. The LD 50 therefore was >2000 mg/kg bw.

Overall:A substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/l, dermal uptake is likely to be low. A molecular Weight less than 100 favours dermal uptake. Above 500 the molecule may be too large. For substances with log P values Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high.

The acute dermal toxicity of Dichloromethylbenze mixture is > 2000 mg/kg bw.

These data indicate a low bioavailability of Dichloromethylbenze mixture.

Estimation of absorption via inhalation:

A not assignable acute inhalation toxicity study is available, but no repeated dose toxicity study.

In an acute inhalation study in male and female Wistar rats the test substance was vapoured dynamicly at temperatures of 20°C, 30°C and 95°C in a time-saturation-test. 200 l air/h where conveyed through 50g test substance. The results were following:

inhalation for 7 h (20°C): no mortality;                                                                                                  

inhalation for 7 h (30°C): no mortality;                                              

inhalation for 3 h (95°C): 2/10 (20 %) of the females died;                

inhalation for 7 h (95°C): 3/10 (30%) animals died. Intoxication symptoms: behaviour disturbance, difficulty of breathing, agitation sedation, irritation of the mucous membranes.

No LC50 was defined.

Overall:Moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed.

These data indicate a low to moderate bioavailability of Dichloromethylbenze mixture.

Estimation of distribution:

In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution. If the molecule is lipophilic (log P >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

Overall, for the absorbed amount of Dichloromethylbenze mixture a wide distribution in the body is assumed.

Estimation of accumulation:

Lipophilic substances have the potential to accumulate within the body. Substances with high    log P values tend to have longer half-lives unless their large volume of distribution is counter-balanced by a high clearance. On this basis, there is the potential for highly lipophilic substances (log P >4) to accumulate in individuals that are frequently exposed (e.g. daily at work) to that substance. Once exposure stops, the concentration within the body will decline at a rate determined by the half-life of the substance.

Dichloromethylbenze mixture has a log Pow of 4.25 (calculated).

Based on the log Pow an accumulation cannot be excluded. However, in the repeated dose toxicity studies no differences in the NOAELs in the subacute and subchronic studies were found. In the subacute repeated dose toxicity study a NOAEL for male rats of 100 mg/kg bw and for female rats the NOAEL of 500 mg/kg bw was found. In the subchronic study the NOAEL for male rats was 100 mg/kg bw and for female rats the NOAEL was 800 mg/kg bw.

Therefore, a low or no accumulation potential is assumed.

Estimation of metabolism:

In vitro and in vivo genotoxicity data of Dichloromethylbenze mixture do not indicate any genotoxic metabolites.

The substance is negative in the absence and in the presence of S9 extracts (Ames test (Bacterial Reverse Mutation Assay) and the HPRT test (In Vitro Mammalian Cell Gene Mutation Test)).

The in vivo MNT (Mammalian Erythrocyte Micronucleus Test) was also negative.

Estimation of excretion:

Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility and ionization of the molecule at the pH of urine.

Substances that are excreted in the bile tend to have higher molecular weights or may be conjugated as glucuronides or glutathione derivatives. Substances in the bile pass through the intestines before they are excreted in the faeces and as a result may undergo enterohepatic recycling.

Other substances excreted in the faeces are those that have diffused out of the systemic circulation into the gastrointestinal tract directly, substances which have been removed from the gastrointestinal mucosa by efflux mechanisms and non-absorbed substances that have been ingested or inhaled and subsequently swallowed.

The characteristics for a favourable urinary excretion are not fulfilled. Based on the low water solubility of 11.2 mg/L and an expected low bioavailability an excretion mainly via faeces is assumed.

Description of key information

There are no experimental toxicokinetic data available for Dichloromethylbenzene (CAS no 29797-40-8) and this statement is based on available data as physico-chemical data and toxicological data. This assumption was conducted based on the REACH ECHA “Guidance on information requirements and chemical safety assessment chapter R.7c” of the ECHA guidance document (Version 3.0, June 2017).

Available physico-chemical information taken into account:

Physical state:

Dichloromethylbenzene mixture is a light yellowish liquid organic substance with a solvent-like odour.

Structure:

Dichloromethylbenzene (CAS no 29797-40-8) = Mixture of the isomers 2,4-dichlorotoluene, 2,5- dichlorotoluene, 3,4- dichlorotoluene, 2,3-dichlorotoluene and 2,6-dichlorotoluene.

Molecular weight:

161.03 g/mol

Water solubility:

11.2 mg/L at 20 °C

Log Pow:

4.25 (calculated)

General considerations:

Absorption is a function of the potential for a substance to diffuse across biological membranes. In addition to molecular weight the most useful parameters providing information on this potential are the octanol/water partition coefficient (log P) value and the water solubility. The  log P value provides information on the relative solubility of the substance in water and the hydrophobic solvent octanol (used as a surrogate for lipid) and is a measure of lipophilicity.    Log P values above 0 indicate that the substance is more soluble in octanol than water i.e. lipophilic and negative values indicate that the substance is more soluble in water than octanol i.e. hydrophilic. In general, log P values between -1 and 4 are favourable for absorption. Nevertheless, a substance with such a log P value can be poorly soluble in lipids and hence not readily absorbed when its water solubility is very low. It is therefore important to consider both, the water solubility of a substance and its log P value, when assessing the potential of that substance to be absorbed.

In general, substances with a log P betweeen -1 and 4 are favourable regarding oral/GI absorption and respiratory absorption. Substance with a logP between1 and 4 favour dermal absorption. Moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed.

Due to the low molecular weight of 161.03 g/mol oral absorption is favoured. A molecular weight less than 100 favours dermal uptake. Above 500 the molecule may be too large.

No information of metabolic transformation of Dichloromethylbenze mixture is available.

Estimation of oral absorption:

In an acute oral toxicity study in male and female Wistar rats, the animals received the Dichloromethylbenze mixture via gavage. Following doses were tested: 1000, 2500, 2650 (only female rats), 3000, 3550, 5000 mg/kg bw. The LD 50 for male rats was 3179 mg/kg and the LD 50 for female rats was 2344 mg/kg bw.

In a subacute OECD Guideline 407 study (Repeated Dose 28-Day Oral Toxicity in Rodents), 5 male and 5 female Wistar-rats per group received 0, 20, 100 or 500 mg of the test substance daily per gavage on 7 days per week for 4 weeks. No substance-related deaths or symptoms were observed. Hematological and clinical-chemical parameter did not show any differences to the control animals. In male and female rats of the 500 mg/kg group a slight increase of liver weight and in male animals a slight hypertrophia of liver cells could be observed. In the epithelia of the kidney tubuli of male rats from 20 mg/kg upwards hyaline droplets were found; this was evaluated as an interaction with alpha-2-microglobulines, which is not relevant for humans. Initially at 500 mg/kg the distended tubuli of the kidney can be seen as a symptom of the early stage of a nephropathy. The NOAEL for male rats was therefore 100 mg/kg bw and for female rats the NOAEL was 500 mg/kg bw.

In a subchronic OECD Guideline 408 study (Repeated Dose 90-Day Oral Toxicity in Rodents), Wistar rats were treated with Dichloromethylbenzene for at least 90 consecutive days by daily. Among all the surviving animals treated with dichloromethylbenzene, the clinical observations revealed a dose dependent incidence of rales and /or hunched posture during the observation period. One female at 100 mg/kg/day showed signs of poor health at the end of the observation period.                                                                                                                                            

For all surviving animals in this study, no toxicologically significant changes were noted in functional observations, ophthalmoscopy, body weight, food consumption and haematology. During histopathological examination morphological changes were noted in kidney, liver, forestomach and thyroid.

Based on the adverse test item-related morphologic alterations in the kidneys of males at 400 mg/kg/day, a No Observed Adverse Effect Level (NOAEL) for Dichloromethylbenzene of 100

mg/kg/day was established for male rats.

For females, adverse test item-related alterations were only noted at 800 mg/kg/day as morphological changes in the liver. Based on these results a No Observed Adverse Effect Level (NOAEL) for Dichloromethylbenzene of 400 mg/kg/day could be considered for female animals.

Overall:Based on the water solubility of 11.2 mg/L absorption following ingestion seems limited. However, any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed. Molecular weights below 500 are favourable for absorption.

The acute oral toxicity of Dichloromethylbenze mixture is > 2000 mg/kg bw and the repeated dose toxicity is moderate (subacute: NOAEL for male rats was 100 mg/kg bw and for female rats the NOAEL was 500 mg/kg bw; subchronic: NOAEL for male rats was 100 mg/kg bw and for female rats the NOAEL was 800 mg/kg bw).

These data indicate a low to moderate bioavailability of Dichloromethylbenze mixture.

Estimation of dermal absorption:

An acute dermal toxicity study is available, but no repeated dose toxicity study.

In an acute dermal toxicity study in male and female Wistar rats the animals were treated with the test substance for 24 h on the shaved back and flank. The dose tested was 2000 mg/kg bw. After 24 h the occlusive coverage was removed and the leftovers of test substance were washed with lukewarm water. Up to 30 minutes after application the female and male animals made sounds. After one hour all animals were symptom-free. No local skin changes were observed. During the 14 day observation-period no animal died. The LD 50 therefore was >2000 mg/kg bw.

Overall:A substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/l, dermal uptake is likely to be low. A molecular Weight less than 100 favours dermal uptake. Above 500 the molecule may be too large. For substances with log P values Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high.

The acute dermal toxicity of Dichloromethylbenze mixture is > 2000 mg/kg bw.

These data indicate a low bioavailability of Dichloromethylbenze mixture.

Estimation of absorption via inhalation:

A not assignable acute inhalation toxicity study is available, but no repeated dose toxicity study.

In an acute inhalation study in male and female Wistar rats the test substance was vapoured dynamicly at temperatures of 20°C, 30°C and 95°C in a time-saturation-test. 200 l air/h where conveyed through 50g test substance. The results were following:

inhalation for 7 h (20°C): no mortality;                                                                                                  

inhalation for 7 h (30°C): no mortality;                                              

inhalation for 3 h (95°C): 2/10 (20 %) of the females died;                

inhalation for 7 h (95°C): 3/10 (30%) animals died. Intoxication symptoms: behaviour disturbance, difficulty of breathing, agitation sedation, irritation of the mucous membranes.

No LC50 was defined.

Overall:Moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed.

These data indicate a low to moderate bioavailability of Dichloromethylbenze mixture.

Estimation of distribution:

In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution. If the molecule is lipophilic (log P >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

Overall, for the absorbed amount of Dichloromethylbenze mixture a wide distribution in the body is assumed.

Estimation of accumulation:

Lipophilic substances have the potential to accumulate within the body. Substances with high    log P values tend to have longer half-lives unless their large volume of distribution is counter-balanced by a high clearance. On this basis, there is the potential for highly lipophilic substances (log P >4) to accumulate in individuals that are frequently exposed (e.g. daily at work) to that substance. Once exposure stops, the concentration within the body will decline at a rate determined by the half-life of the substance.

Dichloromethylbenze mixture has a log Pow of 4.25 (calculated).

Based on the log Pow an accumulation cannot be excluded. However, in the repeated dose toxicity studies no differences in the NOAELs in the subacute and subchronic studies were found. In the subacute repeated dose toxicity study a NOAEL for male rats of 100 mg/kg bw and for female rats the NOAEL of 500 mg/kg bw was found. In the subchronic study the NOAEL for male rats was 100 mg/kg bw and for female rats the NOAEL was 800 mg/kg bw.

Therefore, a low or no accumulation potential is assumed.

Estimation of metabolism:

In vitro and in vivo genotoxicity data of Dichloromethylbenze mixture do not indicate any genotoxic metabolites.

The substance is negative in the absence and in the presence of S9 extracts (Ames test (Bacterial Reverse Mutation Assay) and the HPRT test (In Vitro Mammalian Cell Gene Mutation Test)).

The in vivo MNT (Mammalian Erythrocyte Micronucleus Test) was also negative.

Estimation of excretion:

Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility and ionization of the molecule at the pH of urine.

Substances that are excreted in the bile tend to have higher molecular weights or may be conjugated as glucuronides or glutathione derivatives. Substances in the bile pass through the intestines before they are excreted in the faeces and as a result may undergo enterohepatic recycling.

Other substances excreted in the faeces are those that have diffused out of the systemic circulation into the gastrointestinal tract directly, substances which have been removed from the gastrointestinal mucosa by efflux mechanisms and non-absorbed substances that have been ingested or inhaled and subsequently swallowed.

The characteristics for a favourable urinary excretion are not fulfilled. Based on the low water solubility of 11.2 mg/L and an expected low bioavailability an excretion mainly via faeces is assumed.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential