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Directorate-General for Health and Food Safety
Opinion on the results of the Risk Assessment of: 1,4-DICHLOROBENZENE - CAS N° : 106-46-7 - EINECS N°: 203-400-5. Report version : Draft of March 1999 carried out in the framework of Council Regulation (EEC) 793/93 on the evaluation and control of the risks of existing substances1. Opinion expressed at the 19th CSTEE plenary meeting, Brussels, 9 November 2000.
Terms of reference.
In the context of Regulation 793/93 (Existing Substances Regulation), and on the basis of the examination of the Risk Assessment Report the CSTEE is invited to examine the following issues:
1. Does the CSTEE agree with the conclusions of the Risk Assessment Report?
2. If the CSTEE disagrees with such conclusions, the CSTEE is invited to elaborate on the reasons for this divergence of opinion.
Introduction.
In Europe, the total annual production of 1,4-dichlorobenzene (para-dichlorobenzene : pDCB) is close to 30 000 tons with approximately one half exported outside. It is used in the process of dichloronitrobenzene (a precursor for dyes and pigments) or formulated to air freshners, toilet blocks, and moth repellent. A decreasing consumption is observed since a few years.
GENERAL COMMENTS.
Due to a limited or not adequately conducted discussion of available toxicological data together with the fact that the calculated MOS are to small to be acceptable to this committee, conclusion (ii) of the risk assessment for consumer health is deemed not acceptable by the CSTEE. Similarly, the CSTEE disagrees with the proposal of the rapporteur not to label the substance R 22 (harmful if swallowed) and R 38 (irritating to skin).
The classification of 1,4-dichlorobenzene in group 2B by the IARC should be mentioned in the classification section (p.7) and not only briefly discussed in the text (p.83).
Regarding the environment assessment, the opinion of the CSTEE is that the conclusions of the report have to be reviewed in the light that contrarily to the RAR interpretation and taking into account the data from the original published papers, 1,4-dichlorobenzene is not readily biodegradable but should be regarded as inherently biodegradable. Consequently, the PEC/PNEC should be increased with a factor 4, which leads to PEC/PNEC ratio higher than 1 in most cases. Therefore, conclusion (ii) proposed by the report is not supported by the CSTEE.
In the text, various abbreviations are used for 1,4-dichlorobenzene : pDCB, 1,4-DCB, this should be harmonised.
It is more than unfortunate that, in the list of references, most of the titles are lacking which is a source of confusion. Also, the list of synonyms for 1,4-dichlorobenzene is not given in the general substance information section.
The exposure part is well written, albeit the amount of 1,4-dichlorobenzene formed from higher chlorinated homologues is only mentioned but not quantified.
Environment.
Interpretation of the published data by the CSTEE is that 1,4-dichlorobenzene is not « readily biodegradable » but « inherently biodegradable ». This has major consequences such as multiplying by 4 the PEC/PNEC ratio leading to ratio higher than 1.
The CSTEE agrees with the proposal of the rapporteur for a classification of 1,4-dichlorobenzene with regard to its environmental effects N, R50/53 and S60/61.
Conclusion (ii) for the atmospheric environment is not acceptable because 1,4-dichlorobenzene is of actual concern for atmosphere. To the CSTEE, the conclusion of the risk characterisation related to atmospheric emission should be (i) there is a need for further information and testing, in order to perform an in-depth assessment.
Human Health.
Margins of safety of 13, 35, 14, 14 and 43 that are discussed on page 94 are lower than those that are usually thought to provide full protection to the public. As a consequence, it is the CSTEE understanding that they all indicate a conclusion (iii) there is a need for limiting the risk. These low values for MOS should not be accepted unless there are special, well documented and discussed reasons to do so.
SPECIFIC COMMENTS.
Environment.
Regarding biodegradability, in the Risk Assessment Report two references are cited as a basis for the conclusion to consider 1,4-dichlorobenzene « readily biodegradable ». However, one of these reports (Calamari, Galassi & Setti, 1982) explicitly concluded from the MITI type of tests they had carried out at 8mg of 1,4-dichlorobenzene litre-1, that «1,4-dichlorobenzene cannot be defined as readily biodegradable substance » (on page 375 of Calamari et al ; Ecotox Environm Safety vol 6). Their reason to say so was that biodegradation (based on oxygen consumption and measurement of 1,4-dichlorobenzene concentrations) was only observed at the end of the 28 d observation period (which is twice longer than what is normally done in MITI tests).
The other reference cited in the report, Topping (1987) initially concluded 1,4-dichlorobenzene to be « readily biodegradable » based on the non-detect of 20 mg litre-1 spiked into porous-pot type of activated sludge test (forced aeration). However, the confirmatory test for ultimate biodegradation using 14C-labeled 1,4-dichlorobenzene as substrate, failed to confirm biodegradation (using an unacclimatized sludge carbon dioxide yield was 3%, evaporation was 28%). Therefore, the non-detect from the active sludge system may have been caused by extraction failure. Topping used pentane to extract the wet sludge. It is known that a water non miscible solvent fails to extract lipid soluble substances sorbed into soil or biomass.
In addition, it is known from the work by EAWAG (Duebendorf, Switzerland, cited for instance in the textbook « Environmental Chemistry », by Schwarzenbach et al) that 1,4-dichlorobenzene accumulates from biologically purified municipal waste waters into recipient lake sediments. Therefore, the statement of the Risk Assessment Report, that 1,4-dichlorobenzene would not accumulate, is incorrect.
The risk assessment for the terrestrial (soil) environment has been conducted using toxicity data on plants and soil dwelling invertebrates. The documented possibility of accumulation of 1,4-dichlorobenzene in plants has not been mentioned. The toxicological profile of 1,4-dichlorobenzene does not suggest a particular sensitivity for micro-organisms. The suggested PNEC is appropriate.
The risk for secondary poisoning has also been accounted for. The PNEC oral has been derived on the basis of a chronic study with dogs. On point 3.2.4 the study is reported as an inhalation study, however, information on the route seems to be wrong because in the human health part the NOAEL of 10 mg/kg/d for dogs is described as derived from an oral toxicity study. Therefore the PNEC oral, if indeed derived from an oral toxicity is considered appropriate. In addition, it should be specified in the text that the oral NOAEL for developmental effects has been set from studies with rats. The CSTEE recommends to amend this chapter in order to avoid confusions.
The conclusions of the risk characterisation, regarding low risk for the terrestrial (soil) compartment and for secondary poisoning are acceptable to the CSTEE. Conversely, it is deemed that the need of an in-depth assessment of the potential risk related to atmospheric emission should lead to conclusion (i). It should be also recognised that the substance has biocidal properties (moth repellent) related to its emission in the air, and the mechanisms of action for these biocidal activity should be considered in the risk assessment.
Human Health.
The conclusion (page 92) that sensitisation has not to be discussed is not in line with both the discussion (page 89) that 1,4-dichlorobenzene has a low sensitising potency, and the results of the sensitisation studies discussed on page 69 and 70. An adjuvant type test such as the Magnusson and Kligman should be scored positive if at least 30% of the animals have a positive skin reaction. An open epicutaneous test in which no adjuvant is used should be scored positive with at least 15 % positive animals. Clinical human data are considered positive if there are two independent reports of sensitisation. Using these criteria, 1,4-dichlorobenzene scores negative. It should, however, be noted that in the discussion of the Magnusson and Kligman test (page 70), it is stated that interpretation of the result was difficult because of limitations in conduct. Thus, it can also be argued that the data are inconclusive, which means that there is reason for additional testing with this high production volume chemical. In this case, it is advisable to perform a respiratory sensitisation study in view of the relatively high inhalation exposure of workers.
In the summary of studies in animals (p. 75), it is not clear why a LOAEL of 50 mg/kg/d in female rats for hepatotoxicity as reported in the study by Carlson (1977) has been ignored.
The hepatocarcinogenic effects in mice have not been properly addressed. Although it is described that hepatocellular poliferation occurs at exposure levels below hepatotoxicity it is concluded, that protection from hepatotoxicity protects from tumor induction. Moreover, although the mechanism of hepatocarcinogenicity in mice is unknown, it is concluded on page 91 that "Even if a clear mechanism for the mouse carcinogenicity has not been demonstrated, carcinogenic effects are not considered as relevant to human". The CSTEE does not support this conclusion and recommends further discussion for classification of 1,4-dichlorobenzene in Carc. Cat 3.
A realistic worst case scenario for inhalation exposure is set at 3,3 mg/m3, corresponding to an oral dose of 0.69 mg/kg bw/d with a ventilation rate of 0.7 m3/h, bodyweight of 60 kg and 75% absorption from the lungs. The lowest NOAEL for the critical effect (hepatotoxicity) is 10 mg/kg bw/d in the dog. In the mouse, hepatoxicity is also seen (but at higher doses), as well as liver carcinogenicity which could have liver toxicity and secondary proliferation as an underlying mechanism. No sound arguments are presented for discounting the endpoint liver toxicity as being relevant to man. Since a MOS value of at least 100 is generally considered to be protective, a MOS value of 14 (10/0.69) for 1,4-dichlorobenzene raises some concern.
The conclusion that acute toxicity is of no concern for the consumers seems inadequate to the CSTEE. Poisoning from domestic insecticide (moth repellent) exposure (Cotter, 1953) has been reported and should be discussed in more detail.
The reference list quotes an ATSDR toxicological profile for 1,4-dichlorobenzene published in 1989 whereas a more recent one has been issued in 1993.
----------------------------------------
1 Regulation 793/93 provides a systematic framework for the evaluation of the risks to human health and the environment of those substances if they are produced or imported into the Community in volumes above 10 tonnes per year. The methods for carrying out an in-depth Risk Assessment at Community level are laid down in Commission Regulation (EC) 1488/94, which is supported by a technical guidance document.
Terms of reference.
In the context of Regulation 793/93 (Existing Substances Regulation), and on the basis of the examination of the Risk Assessment Report the CSTEE is invited to examine the following issues:
1. Does the CSTEE agree with the conclusions of the Risk Assessment Report?
2. If the CSTEE disagrees with such conclusions, the CSTEE is invited to elaborate on the reasons for this divergence of opinion.
Introduction.
In Europe, the total annual production of 1,4-dichlorobenzene (para-dichlorobenzene : pDCB) is close to 30 000 tons with approximately one half exported outside. It is used in the process of dichloronitrobenzene (a precursor for dyes and pigments) or formulated to air freshners, toilet blocks, and moth repellent. A decreasing consumption is observed since a few years.
GENERAL COMMENTS.
Due to a limited or not adequately conducted discussion of available toxicological data together with the fact that the calculated MOS are to small to be acceptable to this committee, conclusion (ii) of the risk assessment for consumer health is deemed not acceptable by the CSTEE. Similarly, the CSTEE disagrees with the proposal of the rapporteur not to label the substance R 22 (harmful if swallowed) and R 38 (irritating to skin).
The classification of 1,4-dichlorobenzene in group 2B by the IARC should be mentioned in the classification section (p.7) and not only briefly discussed in the text (p.83).
Regarding the environment assessment, the opinion of the CSTEE is that the conclusions of the report have to be reviewed in the light that contrarily to the RAR interpretation and taking into account the data from the original published papers, 1,4-dichlorobenzene is not readily biodegradable but should be regarded as inherently biodegradable. Consequently, the PEC/PNEC should be increased with a factor 4, which leads to PEC/PNEC ratio higher than 1 in most cases. Therefore, conclusion (ii) proposed by the report is not supported by the CSTEE.
In the text, various abbreviations are used for 1,4-dichlorobenzene : pDCB, 1,4-DCB, this should be harmonised.
It is more than unfortunate that, in the list of references, most of the titles are lacking which is a source of confusion. Also, the list of synonyms for 1,4-dichlorobenzene is not given in the general substance information section.
The exposure part is well written, albeit the amount of 1,4-dichlorobenzene formed from higher chlorinated homologues is only mentioned but not quantified.
Environment.
Interpretation of the published data by the CSTEE is that 1,4-dichlorobenzene is not « readily biodegradable » but « inherently biodegradable ». This has major consequences such as multiplying by 4 the PEC/PNEC ratio leading to ratio higher than 1.
The CSTEE agrees with the proposal of the rapporteur for a classification of 1,4-dichlorobenzene with regard to its environmental effects N, R50/53 and S60/61.
Conclusion (ii) for the atmospheric environment is not acceptable because 1,4-dichlorobenzene is of actual concern for atmosphere. To the CSTEE, the conclusion of the risk characterisation related to atmospheric emission should be (i) there is a need for further information and testing, in order to perform an in-depth assessment.
Human Health.
Margins of safety of 13, 35, 14, 14 and 43 that are discussed on page 94 are lower than those that are usually thought to provide full protection to the public. As a consequence, it is the CSTEE understanding that they all indicate a conclusion (iii) there is a need for limiting the risk. These low values for MOS should not be accepted unless there are special, well documented and discussed reasons to do so.
SPECIFIC COMMENTS.
Environment.
Regarding biodegradability, in the Risk Assessment Report two references are cited as a basis for the conclusion to consider 1,4-dichlorobenzene « readily biodegradable ». However, one of these reports (Calamari, Galassi & Setti, 1982) explicitly concluded from the MITI type of tests they had carried out at 8mg of 1,4-dichlorobenzene litre-1, that «1,4-dichlorobenzene cannot be defined as readily biodegradable substance » (on page 375 of Calamari et al ; Ecotox Environm Safety vol 6). Their reason to say so was that biodegradation (based on oxygen consumption and measurement of 1,4-dichlorobenzene concentrations) was only observed at the end of the 28 d observation period (which is twice longer than what is normally done in MITI tests).
The other reference cited in the report, Topping (1987) initially concluded 1,4-dichlorobenzene to be « readily biodegradable » based on the non-detect of 20 mg litre-1 spiked into porous-pot type of activated sludge test (forced aeration). However, the confirmatory test for ultimate biodegradation using 14C-labeled 1,4-dichlorobenzene as substrate, failed to confirm biodegradation (using an unacclimatized sludge carbon dioxide yield was 3%, evaporation was 28%). Therefore, the non-detect from the active sludge system may have been caused by extraction failure. Topping used pentane to extract the wet sludge. It is known that a water non miscible solvent fails to extract lipid soluble substances sorbed into soil or biomass.
In addition, it is known from the work by EAWAG (Duebendorf, Switzerland, cited for instance in the textbook « Environmental Chemistry », by Schwarzenbach et al) that 1,4-dichlorobenzene accumulates from biologically purified municipal waste waters into recipient lake sediments. Therefore, the statement of the Risk Assessment Report, that 1,4-dichlorobenzene would not accumulate, is incorrect.
The risk assessment for the terrestrial (soil) environment has been conducted using toxicity data on plants and soil dwelling invertebrates. The documented possibility of accumulation of 1,4-dichlorobenzene in plants has not been mentioned. The toxicological profile of 1,4-dichlorobenzene does not suggest a particular sensitivity for micro-organisms. The suggested PNEC is appropriate.
The risk for secondary poisoning has also been accounted for. The PNEC oral has been derived on the basis of a chronic study with dogs. On point 3.2.4 the study is reported as an inhalation study, however, information on the route seems to be wrong because in the human health part the NOAEL of 10 mg/kg/d for dogs is described as derived from an oral toxicity study. Therefore the PNEC oral, if indeed derived from an oral toxicity is considered appropriate. In addition, it should be specified in the text that the oral NOAEL for developmental effects has been set from studies with rats. The CSTEE recommends to amend this chapter in order to avoid confusions.
The conclusions of the risk characterisation, regarding low risk for the terrestrial (soil) compartment and for secondary poisoning are acceptable to the CSTEE. Conversely, it is deemed that the need of an in-depth assessment of the potential risk related to atmospheric emission should lead to conclusion (i). It should be also recognised that the substance has biocidal properties (moth repellent) related to its emission in the air, and the mechanisms of action for these biocidal activity should be considered in the risk assessment.
Human Health.
The conclusion (page 92) that sensitisation has not to be discussed is not in line with both the discussion (page 89) that 1,4-dichlorobenzene has a low sensitising potency, and the results of the sensitisation studies discussed on page 69 and 70. An adjuvant type test such as the Magnusson and Kligman should be scored positive if at least 30% of the animals have a positive skin reaction. An open epicutaneous test in which no adjuvant is used should be scored positive with at least 15 % positive animals. Clinical human data are considered positive if there are two independent reports of sensitisation. Using these criteria, 1,4-dichlorobenzene scores negative. It should, however, be noted that in the discussion of the Magnusson and Kligman test (page 70), it is stated that interpretation of the result was difficult because of limitations in conduct. Thus, it can also be argued that the data are inconclusive, which means that there is reason for additional testing with this high production volume chemical. In this case, it is advisable to perform a respiratory sensitisation study in view of the relatively high inhalation exposure of workers.
In the summary of studies in animals (p. 75), it is not clear why a LOAEL of 50 mg/kg/d in female rats for hepatotoxicity as reported in the study by Carlson (1977) has been ignored.
The hepatocarcinogenic effects in mice have not been properly addressed. Although it is described that hepatocellular poliferation occurs at exposure levels below hepatotoxicity it is concluded, that protection from hepatotoxicity protects from tumor induction. Moreover, although the mechanism of hepatocarcinogenicity in mice is unknown, it is concluded on page 91 that "Even if a clear mechanism for the mouse carcinogenicity has not been demonstrated, carcinogenic effects are not considered as relevant to human". The CSTEE does not support this conclusion and recommends further discussion for classification of 1,4-dichlorobenzene in Carc. Cat 3.
A realistic worst case scenario for inhalation exposure is set at 3,3 mg/m3, corresponding to an oral dose of 0.69 mg/kg bw/d with a ventilation rate of 0.7 m3/h, bodyweight of 60 kg and 75% absorption from the lungs. The lowest NOAEL for the critical effect (hepatotoxicity) is 10 mg/kg bw/d in the dog. In the mouse, hepatoxicity is also seen (but at higher doses), as well as liver carcinogenicity which could have liver toxicity and secondary proliferation as an underlying mechanism. No sound arguments are presented for discounting the endpoint liver toxicity as being relevant to man. Since a MOS value of at least 100 is generally considered to be protective, a MOS value of 14 (10/0.69) for 1,4-dichlorobenzene raises some concern.
The conclusion that acute toxicity is of no concern for the consumers seems inadequate to the CSTEE. Poisoning from domestic insecticide (moth repellent) exposure (Cotter, 1953) has been reported and should be discussed in more detail.
The reference list quotes an ATSDR toxicological profile for 1,4-dichlorobenzene published in 1989 whereas a more recent one has been issued in 1993.
----------------------------------------
1 Regulation 793/93 provides a systematic framework for the evaluation of the risks to human health and the environment of those substances if they are produced or imported into the Community in volumes above 10 tonnes per year. The methods for carrying out an in-depth Risk Assessment at Community level are laid down in Commission Regulation (EC) 1488/94, which is supported by a technical guidance document.
