Registration Dossier

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
DNEL related information
Modified dose descriptor starting point:
T25
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
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
DNEL related information
Modified dose descriptor starting point:
T25
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Comment 

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 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).

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 present OECD test guideline and 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 vapor 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 hemangiosarcoma in male mice and malignant lymphomas in females 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 tumors in the female rat as this was the only tissue where the tumor 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) fulfill the criteria for the application of this model (i.e. study with control and three dose groups, no plateau effect, tumor 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 tumors of the mammary gland in female rats have been identified as the most sensitive response, T25 and BMD10 calculations are performed for all the tumor types in males and females which have shown a statistically significantly increased tumor 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 tumor 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, modeling results for all tumor 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 modeling 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 tumors were combined to reinforce the statistical significance of the dose-response relationship;the statistical incidences of tumors 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 is considered as 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, Denmark). A risk factor of 4*10 -3- defined as a “tolerable risk” - is sometimes used in Europe (e.g. in Netherlands (1997/01WGD for EDC) and Germany (BAUA Announcement 910, 2008).

Currently, 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. Thus, industry would like to draw the attention to the comparison between the apparent carcinogenic risks (potency) of EDC and vinyl chloride monomer (VCM). The proposed SCOEL value for VCM (3 ppm) is based on a risk of 0.9*10-3, derived from epidemiological data. The proposed EDC DMEL 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. Since human data are available for VCM, but not for EDC; therefore a simmlar 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 (reasons mentioned above) and technically not feasible (even when fully complying with the best available techniques).Industry considers that a DMEL value of 1.6 ppm, associated with a potential cancer risk of 4*10-3is tolerable at the current time for the risk assessment, and would like to express a willingness to continue working on the factors around EDC, and to share the results of this work in full transparency with the scientific community and the competent authorities. The establishment of a SCOEL value would be very helpful.

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 unoccluded 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 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
DNEL related information
Modified dose descriptor starting point:
T25
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

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.