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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
6.6 mg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Modified dose descriptor starting point:
T25
Value:
415.1 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
62.4 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
Modified dose descriptor starting point:
T25
Value:
59 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Comments from industry


A new mode of action study for EDC carcinogenicity has been carried out in 2014 and study summaries are included in Sections 7.6.2 and 7.7 of the dossier. The registrants consider the results of this study significant since the study's conclusions do not support a genotoxic mode of action. Such a conclusion will be of interest to any review of the toxicity of 1,2-dichloroethane and the derivation of safe levels of exposure. However, the approach for deriving the safe levels of exposure has not been changed, i. e. the industry approach to derive a DMEL (at a 4*10 -3 risk level) has been maintained (see text below and attached PDF in IUCLID).


 


In addition the alternative approach to derive a DNEL, based on the assumption that a threshold for carcinogenicity exists, has been included (see attached PDF).


 


The RAC recommended dose-response curve for EDC has been included as well. ECHA and RAC recommend to use this dose-response curve in dossiers for the Application of Authorisation in order to calculate the cancer risk for exposure of workers and the general population to 1,2 -dichloroethane (see attached PDF in IUCLID).


 


Selection of the most relevant data for DMEL establishment:


The 2-year inhalation toxicity and carcinogenicity studies in rats and mice published by Nagano et al. (2006) are the most reliable and relevant studies to derive DMELs, since they were performed according to the current  OECD test guideline and under GLP. The mouse and rat carcinogenicity studies, in which 1,2-dichloroethane was administered by oral gavage (NCI, 1978), can only be used for a qualitative assessment of the carcinogenic potential but not for the derivation of the starting dose to establish DMELs because both studies have several limitations such as use of only two dose groups, dose adjustment during the treatment period, no adequate dose setting (no non-toxic low dose group), poor survival in the top-dose, intermittent treatment in the rat study, and a too short treatment period (<= 78 weeks).


 


In the studies reported by Nagano et al. (2006), 50 animals per sex and group were exposed to 1,2-dichloroethane vapour or clean air as control for 104 weeks, 6 hrs/day, 5 days/week. Exposure concentrations were 0, 10, 40 or 160 ppm (v/v) (0, 41.1, 164.5 or 658.1 mg/m³) 1,2- dichloroethane in rats and 0, 10, 30 or 90 ppm (0, 41.1, 123.4 or 370.2 mg/m³) in mice. In rats, subcutaneous fibromas and mammary gland fibroadenomas in males and females, peritoneal mesotheliomas in males, and mammary gland adenomas and adenocarcinomas in females were induced. In female mice, the occurrence of bronchio-alveolar adenoma and carcinoma, uterine endometrial stromal polyps, mammary gland adenocarcinomas and hepatocellular adenomas was considered as treatment-related. Liver haemangiosarcomas in male mice and malignant lymphomas in female mice were not considered as treatment-related since no significant concentration response was present. The most sensitive response was the increased incidence of mammary gland tumours in the female rat as this was the only tissue where the tumour incidence increased with a statistically significant concentration response that was above the historical control range at 40 and 160 ppm and showed a statistically significant increase at 160 ppm in comparison to the control.


 


Calculation of the point of departure (POD) for DMEL establishment


1,2-Dichloroethane was weakly mutagenic in bacterial test systems, but produced clear mutagenic effects in mammalian cytogenetic and gene mutation assays. Metabolic activation is primarily required to cause these effects, which is in line with the known metabolism of the material involving the cytochrome-P450and the glutathione-dependent pathways, where both pathways were considered as possible steps in the bioactivation cascade leading to reactive metabolites. In vivo, 1,2-dichloroethane was not mutagenic in three micronucleus tests, in one dominant lethal test (with certain reservations), and in a GLP Comet assay in mammary epithelial cells after in vivo inhalation exposure of female rats to 200 ppm 1,2-dichloroethane for 4 weeks. Although some evidence of DNA interaction is presented by positive results in an SCE assay and in DNA strand-break assays, based on the available data, in vivo evidence for a DNA-reactive Mode of Action is not convincing, especially given the recent in vivo negative Comet results in target tissue from the high-dose repeated exposure MOA study. However, as no definitive proof is available yet for a non-genotoxic (i. e., threshold) alternative mode of action for 1,2-dichloroethane-induced mammary tumours, a DMEL approach with a linear extrapolation from high dose to the low dose (‘linearized approach’), has been applied.


In accordance with the ECHA Guidance on information requirement and CSR, chapter R.8 (2008), the T25 is calculated as the point of departure according to the method described by Sanner et al. (2001) and Dybing et al. (1997). In addition, the BMD10 is calculated using the EPA benchmark model software (BMDS 2.1.1), since the experimental data (from the long-term inhalation study by Nagano et al. 2006) fulfil the criteria for the application of this model (i.e. study with control and three dose groups, no plateau effect, tumour incidence in more than two treatment groups below 100%). The multistage model is used since 1,2-dichlorethane is supposed to be a non-threshold carcinogen whose metabolites interact directly with DNA. It should be noted that at current time there is no proof that EDC act as non-threshold carcinogen, but as there is only limited, no definitive proof that it does not, the most conservative approach is used. The multistage model is also recommended in the ECHA Guidance on information requirement and CSR, chapter R.8 (2008). Even though tumours of the mammary gland in female rats have been identified as the most sensitive response, T25 and BMD10 calculations are performed for all the tumour types in males and females which have shown a statistically significantly increased tumour incidence. This procedure is in line with the ECHA Guidance on information requirement and CSR, chapter R.8 (2008). The results are shown in the following tables.


 


Table 1. Calculation of T25 as point of departure for DMEL establishment.


 







































































































 



Tumor



Conc*



Tumor incidence [%]



T25



Species



Sex



Organ



Type



[ppm]



Control



Conc



[ppm]



 



 



 



 



 



 



 



 



rat



m



mammary



fibroadenoma



160



0



10



400



 



m



mammary



combined**



160



2



14



327



rat



f



subcutis



fibroadenoma



160



0



10



400



 



 



mammary



adenoma



160



6



22



235



 



 



 



fibroadenoma



160



8



26



204



 



 



 



combined**



160



14



44



115



 



 



 



combined***



160



16



50



99



* : lowest concentration with a statistically significantly increased tumour incidence


**: fibroadenoma & adenoma


***: fibroadenoma, adenoma & adenocarcinoma


 


 


Table 2. Calculation of BMD10 as point of departure for DMEL establishment


 




























































































































 



 



Model



BMD10



BMDL10



AIC



p-value



chi^2



Species



Sex



Organ



Type



 



ppm



ppm



 



 



 



 



 



 



 



 



 



 



 



 



 



rat



m



mammary



fibroadenoma



ms



158



100



47



0.89



0.23



 



m



mammary



combined**



ms



149



85



82



0.70



0.72



rat



f



subcutis



fibroadenoma



ms



158



100



47



0.89



0.23



 



 



mammary



adenoma



ms



102



52



47



0.53



0.39



 



 



 



fibroadenoma



ms



79



43



141



0.11



2.6



 



 



 



combined**



ms



42



25



205



0.52



0.42



 



 



 



combined***



ms



52



23



216



0.85



0.04



ms: multistage model


**: fibroadenoma & adenoma


***: fibroadenoma, adenoma & adenocarcinoma


 


Using the BMD approach, modelling results for all tumour types satisfy the quality criteria for goodness-of-fit (p>0.1, chi-square between -2 and +2) and uncertainty (BMD/BMDL ratio below 10), with the exception of mammary fibroadenoma in female rats (chi-square >2). The lowest BMD10 and T25 values of 42 ppm and 99 ppm, respectively (obtained for the modelling of combined fibroadenoma and adenoma and combined fibroadenoma, adenoma and adenocarcinoma in female rats, respectively), are selected as the most conservative point of departures for the DMEL derivation.


 


Derivation of the DMEL for long term inhalation and dermal exposure (systemic effects) of Workers


 


Inhalation DMEL


For workers, light activity is assumed during the exposure time of 8 hrs per day, 5 days per week, 48 weeks per year for 40 years.


 


The selected BMD10 and T25 value (sel. POD) of 42 and 99 ppm, respectively, are adjusted accordingly (corr. POD = sel. POD x 6 hrs/8 hrs x 52 wks/48 wks x 75 yrs/40 yrs x 6.7 m³/10 m³) resulting in corrected points of departure (corr. POD) of 42.9 ppm (corr. BMD10) and 101 ppm (corr. T25). To derive the DMEL for long term inhalation exposure representing a 1 per 100'000 lifetime risk of cancer (1*10-5risk), the corrected BMD10 or T25 value have to be divided by the high-to-low-dose-risk-extrapolation-factor (HtLF) of 10'000 and 25'000 for respectively the BMD10 and the T25 (“linearised” approach). This results in a DMEL long term inhalation (lifetime cancer risk 1*10-5) = corr. BMD10 / 10'000 = 42.9 ppm / 10'000 = 0.00429 ppm or 17.6 μg/m³ or a DMEL long term inhalation (lifetime cancer risk 1*10-5) = corr. T25 / 25;000 = 101 ppm / 25000 = 0.00404 ppm or 16.6 μg/m³


 


The DMEL (lifetime cancer risk 1*10-5) of 17.6 μg/m³ derived from the corrected BMD10 is close to that derived from the corrected T25 (i.e. of 16.5 μg/m³). This justifies the use of only one; thus the corrected T25 value of 101 ppm is taken into account since the use of this value results in a slightly lower DMEL.


 


Discussion


The application of the default REACH guidance, which defines the DMEL as the concentration leading to an excess cancer risk of 1*10 -5, leads to a DMEL of 0.004 ppm i.e. 16.6 µg/m3.


 


The suspected relationship between the carcinogenic response of 1,2-dichloroethane,and the associated risk has to be carefully considered for the following reasons: only one long-term inhalation study with 1,2-dichloroethane (two species) is available in which different types of mammary tumours were combined to reinforce the statistical significance of the dose-response relationship; the statistical incidences of tumours in the animal population are linearly extrapolated into lower dose ranges which are more likely to occur in the work-place. However, this linear extrapolation is somewhat conservative since at very low doses there is no proof that a carcinogen mechanism is observed; and finally no epidemiological data seem to confirm the carcinogenic nature of 1,2-dichloroethane in humans. In conclusion, the DMEL of 0.004 ppm (16.6 µg/m3) is considered as very conservative.


 


The following DMELs values are presented for different lifetime cancer risks, from the corrected T25 of 101 ppm (1 ppm = 4.11 mg/m³):


 


 


 


 





























































Life time cancer risk



Corrected T25 (ppm)



Extrapolation factor



DMEL



 



 



 



ppm



mg/m³



 



 



 



 



 



4*10-3



101



62.5



1.6



6.64



1*10-3



101



250



0.404



1.66



4*10-4



101



625



0.16



0.664



1*10-4



101



2500



0.0404



0.166



1*10-5



101



25000



0.00404



0.0166



 


As an alternative approach to a DMEL associated to a cancer risk of 1*10-5, it is proposed to base a DMEL on a cancer risk factor of 4*10-3, which leads to a DMEL of 1.6 ppm. This value is broadly in line with the national OELs of Nordic countries (1 ppm for Sweden, Norway, Finland and Denmark). A risk factor of 4*10 -3- is sometimes used in other European countries (e.g. in Netherlands (Dutch Expert Committee on Occupational Safety (DECOS, 2019) and Germany (BAUA Announcement 910, 2008). DECOS estimates that the concentration of 1,2-dichloroethaane in the air that corresponds to an extra risk of cancer of 4 per 1,000 (the prohibitive risk level) equals to 12.6 mg/m3, based 40 years of occupational exposure.


Recently, the EU Scientific Committee on Occupational Exposure Limits (SCOEL) concluded - on the basis of the available information including scientific and technical data - that it is possible to set a limit value for 1,2-dichloroethane. SCOEL identified also the possibility of significant uptake through the skin. It is therefore appropriate to establish a limit value for 12,-dichloroethane (2 ppm, 8.2 mg/m3) and to assign to it a skin notation in Annex III to Directive (EU) 2019/130 of 16 January 2019 amending Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work.


The industry is taking practical measures to minimize exposure to EDC and thus minimize the cancer risk as far as is practical, as specified in the current version of the Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work. Furthermore, it may be interesting to further refine the cancer risk estimate and investigate more on the toxicology of EDC. The proposed DMEL for EDC is based on risk of 4*10-3, which depends only on animal data. The situation for both substances is comparable due to analogous chemical structures. Human data are available for VCM, but not for EDC; therefore a similar range of cancer risk may be assumed for EDC based on read-across.


In conclusion, a DMEL of 0.004 ppm is considered both scientifically questionable and technically not feasible, even when fully complying with the best available techniques. The industry considers that a DMEL value of 1.6 ppm (6.6 mg/m3), associated with a potential cancer risk of 4*10-3 , is acceptable at the current time for the risk assessment and is broadly in line with the limit value of 2 ppm (8.2 mg/m3) established by the SCOEL (Directive 2004/37/EC).


Dermal DMEL


It is proposed to proceed with a route to route extrapolation to calculate the dermal DMEL.


Dermal absorption through human skin in vitro has been studied by Ward (1998). The most relevant experimental design for the human dermal exposure scenario has been the un-occluded application of 5 or 10 μl of 1,2-dichloroethane/cm² (corresponding to 6.2 and 12.4 mg/cm², respectively) to human skin disks for up to 8 hours, resulting in an absorption rate of 92 or 82 μg/cm²/hr, respectively. Absorption had virtually ceased by 0.25 hours which is due to the volatility of 1,2-dichloroethane (vapour pressure of 81.3 hPa at 20°C) resulting in a rapid evaporation of the substance following dermal exposure. Based on this data, the penetration of 92 μg/cm² after dermal exposure to 6.2 mg/cm² is taken as a realistic worst case for dermal absorption. This corresponds to the absorption of 1.5 % of the applied dose.


Considering that the worker inhalation exposure of 101 ppm (= 415.1 mg/m³) during a 8-hour work shift corresponds to a systemic dose of 436 mg/m³ x 10 m³ / 70 kg = 59 mg/kg bw/d (using the default assumption of 100% inhalation absorption), the dermal dose in humans is 59 mg/kg bw/d / 0.015 (skin penetration human) = 3953 mg/kg bw/d.


The dermal DMEL is 3953/(25000) = 0.156 mg/kg bw/d for the 10-5risk (the allometric scaling factor was implicitly taken into account). Considering a risk of 4*10-3 (same reasons as mentioned above), the dermal DMEL for workers is 62.4 mg/kg bw/d.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
2.9 µg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
Modified dose descriptor starting point:
T25
Value:
72.7 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

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:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Derivation of the DMEL for long term inhalation exposure (systemic effects) of the general population


The selected BMD10 and T25 value (sel. POD) of 42 ppm and 99 ppm, respectively, are adjusted to a 24-hour per day, 7 days per week lifetime exposure of the general population to obtain the corrected dose point of departure (corr. POD) of 7.5 ppm (corr. BMD10) and 17.7 ppm (corr.T25) (corr. POD = sel.POD x 6 hrs/24 hrs x 5 d/7 d).To derive the DMEL for long term inhalation exposure based on a 1 per 100'000 lifetime risk for cancer, the corrected BMD10 and T25 value have to be divided by the high-to-low-dose risk-extrapolation-factor (HtLF) of 10'000 and 25'000, respectively (the linearized approach is used)


 


DMEL (long term inhalation) = corr. BMD10/10'000 = 7.5 ppm /10000 = 0.00075 ppm or 3.1 μg/m³ for an extra cancer risk of 1*10-5 and DMEL (long term inhalation) = corr. T25/25'000 = 17.7 ppm /25'000 = 0.00071 ppm or 2.9 μg/m³ for an extra cancer risk of 1*10-5. The results show that the application of the BMD model yields a DMEL which is very similar to the one derived on the basis of the T25 concept.

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