Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.4 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.4 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.8 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.4 mg/m³
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

Chronic effects: Workers

Local effects

Inhalation route

The critical local effects following chronic inhalation exposures to chloroprene are considered to be non-neoplastic lesions of the nose and the lungs. In 2-year chronic inhalation bioassays conducted by NTP (1998), the incidence of non-neoplastic lesions of the lungs (bronchiolar hyperplasia or alveolar epithelia hyperplasia) and of the nose (chronic inflammation; atrophy or necrosis) were statistically increased in mice and rats treated at the lowest exposure concentration in the study (12.8 ppm). Since a No-Observed-Adverse-Effect-Concentration (NOAEC) was not identified in the study, a suitable point of departure (POD) to inform the derivation of a DNEL for local effects was determined using benchmark-dose modelling corresponding to a predicted 5% response level from the available bioassay data. Since benchmark dose modelling is considered to provide a more robust analysis of the dose-response relationship to inform risk characterisation compared to use of Assessment Factors using the NOAEC, this approach is preferred to the use of the LOAEC as the starting point for the DNEL derivation. For purposes of comparison and completion, an assessment based on the Lowest-Observed-Adverse-Effect-concentration (LOAEC) of 12.8 ppm has also been included.

DNEL derived using Benchmark-dose modelling

Where a NOAEL cannot be identified from an experimental animal study, REACH guidance proposes that the lower 95% confidence interval of the 5% benchmark dose (BMD5%) be used; the BMDL5%can be regarded as comparable to the NOAEL (where the BMD5%is the effective dose evoking an adverse response in 5% of experimental animals). This approach is deemed preferable to the use of a LOAEC for determining a suitable POD since it takes into account the respiratory effects dose-response induced by chloroprene in experimental animals and obviates the uncertainty associated with using an assessment factor to reflect the relationship between the LOAEC and the NOAEC.

The US Environmental Protection Agency Benchmark Dose (EPA BMD) software version 2.1.2 was used to fit a selection of dose-response models to the NTP bioassay data for local non-neoplastic endpoints (e.g. non-systemic effects observed in the nose and the lungs) considered to be candidates for the critical effect, notably those endpoints which showed a statistically significant increase at the lowest exposure concentration tested and a dose-dependent response. Non-neoplastic effects which did not meet these criteria (e.g. basal cell hyperplasia and fibrosis of the olfactory epithelium) were excluded from the analysis. Since the NTP bioassay data consisted of two categories: affected and non-affected, the data were regarded as dichotomous (e.g. quantal). The goodness-of-fit of models (Gamma, Logistic, LogLogistic, LogProbit, Multistage, Probit, Weibull and Quantal-Linear) against the data was assessed by considering the p-value in relation to the critical value (a = 0.1); visual plots and ranking using the Akaike Information Criterion. 

In order to derive a DNEL for local effects relevant to workers the BMDL5%values were adjusted as follows:

 

1.     BMDL5%values expressed in ppm were converted to mg/m3(where 1 ppm of chloroprene = 3.62 mg/m3)

2.     Experimental animals were exposed for 6 hours/day. BMDL5%values were adjusted to reflect a typical working day of 8 hrs, 5 days/week: BMDL5% x 6/8 x 5/5.

3.     BMDL5%values were corrected to account for the difference between respiratory rates under standard conditions (sRV: 6.7 m3/day) and under conditions of light activity (wRV: 10 m3/day): BMDL5% x sRV/wRV.

The following assessment factors were applied to the adjusted BMDL5%values (giving an overall assessment factor of 3):

Interspecies :  Guidance from REACH indicates that an assessment factor for allometric scaling to account for metabolic differences between species is not required since an inhalation DNEL is being derived from an animal inhalation study (i.e., allometric scaling factor of 1). Thus, a factor of 1 was applied.

 For addressing remaining interspecies differences, two issues were considered. Firstly, marked toxicodynamic differences are likely to exist between rodents and humans since the critical effect, nasal degenerative changes, occurs in rodents, which are obligate nose breathers. This will result in a comparatively higher deposited dose of chloroprene in the rodent nose than in humans, which are oro-nasal breathers. Secondly, according to ECETOC guidance (2003), routine application of a factor of 2.5 for remaining differences is not scientifically justified (Batke et al, 2010). Thus, a factor of 1 was applied for remaining differences. 

The composite assessment factor for interspecies differences is 1.

 

Intraspecies:  Guidance from ECETOC (ECETOC 2010) indicates that an assessment factor of 3 is appropriate to account for the inter-individual differences between workers.

Exposure duration: A factor of 1 was applied: a chronic study was used as the basis for the DNEL.

Dose-response:  A factor of 1 was applied: a BMDL5%was used as basis for the DNEL.

Quality of the database:  A factor of 1 was applied: the database is comprehensive and of good quality.

 

Table X gives BMD5%and BMDL5%values predicted using best-fit models for non-systemic, non-neoplastic lesions observed in rats and mice in the 2-year NTP bioassay studies; adjusted BMDL5%values (e.g., for exposure duration, light exercise and respiratory rates) and the corresponding DNEL values derived by the application of assessment factors discussed previously to the adjusted BMDL5%values.

On the basis of the benchmark-dose modelling of the 2-year rodent bioassay data, the most sensitive endpoint was considered to be nasal degenerative lesions in male rats (epithelial necrosis). As obligate nasal breathers, rodents may be more susceptible to nasal toxicity after exposure to inhalants. The quantitative relevance of these observations to humans, who are oronasal breathers is therefore unclear and a DNEL derived solely on this basis may overestimate the threshold for local respiratory effects in humans.

The lowest chronic DNEL value for local effects was therefore predicted to be 0.8 mg/m3based on nasal necrosis in male rats. 

A chronic DNEL of 0.8 mg/m3(0.22 ppm) is proposed for the local respiratory effects of chloroprene in workers

 

Table X: BMD5%, BMDL5%,adjusted BMDL5%and DNEL values predicted using the EPA BMD model for local non-neoplastic effects observed in the NTP (1998) 2-year bioassays.

End-point

Species (sex)

Best-fit model

LOAEC (ppm)

BMD5%(ppm)

BMDL5%(ppm)

Adjusted POD (mg/m3)

DNELa(mg/m3)

Nasal effects

Chronic inflammation

Rat (m)

Log-logistic

12.8

30

24.2

43.9

14.6

Atrophy

Rat (m)

Log-logistic

12.8

8.3

6.0

11.0

3.6

Necrosis

Rat (m)

Multi-stage

12.8

1.8

1.3

2.4

0.8

Lungs

Alveolar epithelial hyperplasia

Rat (m)

Log-logistic

12.8

2.3

1.5

2.7

0.9

Alveolar epithelial hyperplasia

Rat (f)

Log-logistic

12.8

5.4

3.3

6.1

2.0

Bronchiolar hyperplasia

Mouse (m)

Multi-stage

12.8

2.8

2.0

3.6

1.2

Histiocystic infiltration

Mouse (f)

Multi-stage

12.8

2.5

1.7

3.1

1.0

aTotal assessment factor applied = 3

 

 

Dermal route

The critical local effect of dermal exposure to chloroprene is skin irritation, for which a threshold has not been identified. Prolonged, dermal contact cannot be tolerated and occupational exposures to chloroprene should be controlled by the use of appropriate personal protective equipment and good industrial hygiene to prevent skin irritation. A long-term DNEL for local effects following dermal exposures is not therefore derived.

Systemic effects (cancer)

Inhalation route

Under REACH, human data as well as non-human data have to be considered (Annex I, 1.02-1.2). For chloroprene, a robust observational epidemiology study is available. As these data are of high relevance for the human risk assessment and the generation of a Chemical Safety Report, these data have been evaluated in the context of DNEL and DMEL derivation (in line with ECHA Guidance R.8, 8.5.1, even if final guidance from an ECHA guidance document for derivation of DNEL/DMEL from human data is not yet available).  For purposes of comparison, a DMEL was also derived based on the animal bioassay data following standard approaches set out in REACH guidance.

As defined in the REACH Guidance Document R8, in case of a substance with a carcinogenic potential in animals or humans, one requirement is to determine whether the substance exerts the effects by a threshold or non-threshold mode of action (TGS R.8, Figure R.8-1). For chloroprene, animal data points to a carcinogenic potential but contemporary human epidemiology data do not. The mode of carcinogenicity in animals is unknown. The absence of a genotoxic potential indicate that non-genotoxic events occur.

In a chronic inhalation toxicology study of chloroprene in rats and mice, significant increases in neoplasms of the lung and kidney are reported (NTP, 1998; Melnick et al., 1999). The observation of respiratory tract tumors in rodents is noteworthy in that it suggests that these neoplasms are relevant to humans since the exposure route of greatest concern in the workplace is the lungs via inhalation (Scott 1995). Since the rodent respiratory tract tumors may represent either direct acting effects on the lung from inhalation or indirect effects arising from circulatory exposure to chloroprene metabolites from the liver, lung tumors will be considered to represent systemic toxicity. Using Benchmark Dose analysis, Melnick et al. (1999) concluded that the most sensitive sex, species and target organ was female mouse lung tumours. Studies on the metabolism of chloroprene in vitro suggest that the mouse is at considerably more risk for toxicity than other species. Although the full mechanism leading to tumour development in the lung or other tissues is not completely understood chloroprene metabolism, specifically its greater oxidation leading to epoxides or other reactive metabolites, slower epoxide hydrolysis, and the potential for glutathione depletion in the mouse relative to other species, indicates that the mouse is not an appropriate model for human health risk assessment. Species differences in tumour outcome are also supported by the lack of lung and liver tumors in other rodent species where observed activation:detoxication ratios are lower than for mice e.g. Wistar rat and Syrian Golden hamster (Trochimowicz et al., 1998). This lack of species similarity in response is also seen in the outcome of the latest human epidemiology studies were no significant increase in lung or liver cancer deaths were reported (Marsh et al. 2007). Collectively, these data show that the mouse is not a good predictor for human outcome. 

In contrast to the animal data, observational epidemiology studies of workers exposed at chloroprene manufacturing sites do not show chloroprene to be causally associated with cancer mortality. Although a mode of action for genotoxicity or rodent carcinogenicity of chloroprene has not been established (Pagan, 2007), an approach is needed to identify a predicted human cancer risk for chloroprene for purposes of REACH risk assessment. A review study of available observational epidemiological studies concluded the weight of evidence does not support a substantial association between chloroprene exposure and cancer (Bukowski 2009).

Taking these issues into consideration, an approach to derive a no adverse-effect level (NOAEL) for chloroprene exposure based on observational epidemiology data is described. As the NOAEL in humans can be considered as the point of departure for both the DNEL and DMEL derivation, this approach is intended to cover both aspects. The approach taken was based on: (1) the lack of association of a significant relative increase in cancer mortality risk from a meta-analysis of key occupationally exposed cohorts identified by Bukowski (2009); (2) the guidance from REACH indicating that robust and reliable human exposure and epidemiology data is preferred over other (i.e., animal) data[1]; and (3) the assumption that chloroprene is carcinogenic to humans for this derivation despite the negative findings from a review of published epidemiology studies.

Derivation of DNEL/DMEL based on epidemiological data

The occupational epidemiological study by Marsh et al (2007a,b: referred to as the Marsh study) of workers from four chloroprene production cohorts was considered to be the most methodologically rigorous study by a recent qualitative assessment using published EPA criteria for the interpretation of epidemiology studies for risk assessment (Bukowski 2009). The qualitative review by Bukowski concluded that the Marsh study provided the highest quality evidence and should serve as the principal study for chloroprene risk assessment. The Marsh study included a total population of 12,430 workers across four site locations, with a large proportion of workers employed for 20 or more years in production processes, and nearly complete cohort enumeration with cross-validation reported. The quality of exposure data in the Marsh study was also highly rated as the researchers used a rigorous and innovative exposure assessment method based on chemical process exposure reconstruction. The potential effects of smoking and other possible confounders were evaluated using local county mortality comparison and workers’ pay type. 

Taking this into consideration, the Marsh et al study was selected as the basis for meta-analysis to inform the derivation of a human DNEL/DMEL. The derivation of a No Adverse-Effect Level from data in Marsh et al is described in the report by Le and Symons, 2010.

Meta-analysis was conducted using relevant human data from the Marsh study. Respiratory system cancer mortality was considered to be the most relevant possible health outcome since animal studies of chloroprene indicate that lung tumours are the most sensitive endpoint for purposes of risk assessment (i.e., indicates the lowest benchmark dose). The results of the meta-analysis indicate that a time-weighted average exposure of 1.96 ppm (6.4 mg/m3) is an appropriate NOAEC for chloroprene. This value corresponds to a NOAEC derived from empirical analyses of human worker data since no statistically significant of excess respiratory cancer mortality risk is observed at the highest cumulative exposure levels reported by the Marsh study.  

According to the DRAFT ECHA Guidance on Derivation of DNEL/DMEL from human data (February 2010) the same two options available for deriving a DMEL from animal data (i.e., linearized approach and large assessment factor approach) can be applied to the derivation of a DMEL based on human data. Steps to be considered are: the selection of the relevant dose descriptor; modification, if necessary and the selection and Justification of the Assessment Factors – in this case intraspecies differences and quality of the database[2].

Since the dose descriptor is a NOAEC from comprehensive epidemiological studies, modification for route to route extrapolation or differences in exposure conditions for workplace exposure are not required. As large populations were evaluated in the epidemiology studies, an intraspecies factor is also not needed. Regarding quality of the database, Bukowski (2009) identified the Marsh study as representingthe highest quality study for purposes of human risk assessment.

The followingassessment factors were applied to the NOAEC (giving an overall assessment factor of 3):

 

Interspecies:  A factor of 1 was applied: human data have been used

Intraspecies: Guidance from ECETOC (ECETOC 2010) indicates that an assessment factor of 3 is appropriate to account for the inter-individual differences between workers. In addition, the NOAEL was derived based on large populations of workers.

Nature of carcinogenic

Process:  A factor of 1 was applied to account for uncertainty in the carcinogenic process.  Animal studies suggest carcinogenic potential, but no clear genotoxic potential is seen in standard genotoxicity assays.  No carcinogenic potential is evident from contemporary, high quality occupational epidemiology studies.   Marked species differences in chloroprene metabolism are seen with the conclusion that mice are not a good predictor of human response.  Since the mode of action does not show both genotoxic and carcinogenic activity, no assessment factors is needed for the nature of the carcinogenic processThe point of comparison

(BMD is not a NOAEL):  A factor of 1 was applied: a NOAEC was used as a starting point for the derivation and the basis for the chloroprene meta-analysis was to assume there was a dose response relationship when none existed.

Applying an overall assessment factor of 3 to the NOAEL of 6.4 mg/m3(1.96 ppm) derived from the meta-analysis of human data from the Marsh et al study gives a DNEL/DMEL of 2.4 mg/m3(0.65 ppm) for workers.

A chronic inhalation DNEL/DMEL of 2.4 mg/m3 (0.65 ppm) is proposed for the risk of cancer in workers, reflecting a low likelihood of effects and a level of risk that can be regarded as of low concern.

In addition it is important to note that the DNEL for local effects is lower (0.8 mg/m3) and risk management measures will be based on that lower DNEL for local effects, comparted to the DNEL for carcinogenicity (2.4 mg/m3)

Derivation of DMEL based on 2-year chronic inhalation bioassays

As discussed previously, the derivation of a DNEL/DMEL based on human data is the more relevant approach since data are available from good quality epidemiological studies and rodent models may not always be appropriate for human health risk assessment. For purposes of comparison, a DMEL was also derived based on the animal bioassay data following standard approaches set out in REACH guidance.

In rodent studies, the critical systemic effects after chronic inhalation exposures to chloroprene are tumours occurring at different sites. In 2-year chronic inhalation bioassays conducted by NTP (1998) incidence of tumours of the lungs (alveolar and bronchiolar adenoma or carcinomas), the skin (sarcomas), the mammary gland (adenocarcinomas, carcinomas) and of the hardarian gland (adenomas or carcinomas) were statistically increased in mice, whereas incidence of tumours of the oral cavity (papillomas or carcinomas), the thyroid gland (follicular cell adenomas or carcinomas), the mammary gland (adenocarcinomas, carcinomas) and of the lung (alveolar and bronchiolar adenoma or carcinomas) were statistically increased in rats.

Since the carcinogenic mode of action of chloroprene has not been fully elucidated and it is not known with certainty whether this substance is a threshold or a non-threshold carcinogen, a Derived Minimal Effect Level (DMEL) rather than a DNEL has been derived for systemic effects following chronic inhalation occupational exposures. A DMEL is a risk-related reference value, below which exposures can be regarded as of low concern which can be used to better target risk management measures. REACH guidance indicates there are two semi-quantitative approaches for deriving a DMEL from animal data: the linearised approach and the large assessment factor approach. On the basis that adequate animal cancer data to define a dose-response relationship are available from the NTP bioassay studies and that the use of the lower confidence interval of a benchmark dose as the POD takes the quality of the dataset into account, the large assessment factor approach was selected as the preferred approach to derive a DMEL from animal data. This approach was only done for purposes for comparing these results to the preferred DNEL/DMEL calculation based on human data.

The derived DMEL represents an exposure level for workers associated with a low likelihood of effects, for which lifetime cancer risks can be regarded as of low concern. In the large assessment factor approach, the point of departure is taken as the lower level of the 95% confidence interval around the BMD corresponding to a 10% response in bioassay studies (e.g. BMDL10%). In order to derive a DMEL for systemic effects relevant to workers based on rodent bioassay data the BMDL10%values for different tumour types were adjusted as follows:

1.     BMDL10%values expressed in ppm were converted to mg/m3(where 1 ppm of chloroprene = 3.62 mg/m3)

2.     BMDL10% values were adjusted to reflect working-life exposures for workers, typically exposed for 8 hours per day, 5 days per week, for 48 weeks per year for 40 years: POD x 6/8 x 5/5 x 52/48 x 75/40.

3.     BMDL10%were corrected to account for the difference between respiratory rates under standard conditions (sRV: 6.7 m3/day) and under conditions of light activity (wRV: 10 m3/day): POD x sRV/wRV.

 

Absorption of chloroprene following inhalation exposure is expected to be high. No published experimental data exist that provide a direct measurement of absorption during inhalation exposure. While REACH guidance proposes that 100% absorption by inhalation is assumed, basic metabolism and kinetic information developed on chloroprene would suggest the actual value is much lower. As an alternative approach, the physiologically-based kinetic model for chloroprene, developed by Himmelstein et al. (2004b), was used to estimate inhalation absorption. Assuming a 1 ppm (24 hr/day x 5 days) chloroprene exposure, at steady state, the percent of chloroprene absorption by inhalation was estimated to be 64.3%, 53.7% and 53.6% in the mouse, rat, and human, respectively, (calculated as amount inhaled – amount exhaled)/amount inhaled * 100%). Concordance among species is reasonable and the findings are consistent with the understanding that the key determinants of absorption are ventilation, blood-to-air partition coefficients and metabolism based on the results of the published parameter sensitivity analysis (Himmelstein et al., 2004b).

 

The following assessment factors were applied to the adjusted BMDL10%derived using the large assessment factor approach (giving an overall assessment factor of 30):

 

Interspecies :  A factor of allometric scaling was not applied since an inhalation DNEL is being derived based on an inhalation animal study.

 For addressing remaining interspecies differences, two factors were considered. One, marked toxicodynamic differences are likely to exist between rodents and humans since the critical effect, nasal degenerative changes, occurs in rodents, which are obligate nose breathers. This will result in a comparatively higher deposited dose of chloroprene in the rodent nose than in humans, which are oro-nasal breathers. Second, per ECETOC guidance (2003), routine application of a factor of 2.5 for remaining differences is not scientifically justified (Batke et al, 2010). Thus, a factor of 1 was applied for remaining differences. 

The composite assessment factor for interspecies differences is 1.

Intraspecies: Guidance for REACH indicates that an assessment factor of 3 is appropriate to account for the inter-individual differences between workers

Nature of carcinogenic

Process:  A factor of 1 was applied to account for uncertainty in the carcinogenic process.  Animal studies suggest carcinogenic potential, but no clear genotoxic potential is seen in standard genotoxicity assays.  No carcinogenic potential is evident from contemporary, high quality occupational epidemiology studies.   Marked species differences in chloroprene metabolism are seen with the conclusion that mice are not a good predictor of human response.  Since the mode of action does not show both genotoxic and carcinogenic activity, no assessment factors is needed for the nature of the carcinogenic process

The point of comparison

(BMD is not a NOAEL):  A factor of 10 was applied to take into account that the BMD relates to a response and cannot be regarded as a surrogate for a threshold

The US EPA BMD model was used to fit a selection of dose-response models to the NTP bioassay data for tumours observed at different sites in mouse and rat studies. Since the NTP bioassay data consisted of two categories: affected and non-affected, the data were regarded as dichotomous (e.g. quantal). The goodness-of-fit of models (Gamma, Logistic, LogLogistic, LogProbit, Multistage, Multi-stage-cancer, Probit, Weibull and Quantal-Linear) against the data was assessed by considering the p-value in relation to the critical value (a = 0.1); visual plots and ranking using the Akaike Information Criterion. 

Table X gives BMD10%and BMDL10%values predicted using best-fit models for tumours observed in rats and mice in the 2-year NTP bioassay studies and the corresponding DMEL values derived by adjusting for working-life exposures, light exercise and respiratory rates and the application of assessment factors as discussed previously. 

The analysis of tumour incidence data from 2-year chronic bioassay studies in rats and mice conducted by the NTP (1998) using benchmark dose modelling predicts that tumour sensitivity is greatest in mice towards alveolar and bronchiolar adenomas and carcinomas. Lower BMDL10%values were obtained for these tumour types in mice, than for other tumours in mice or in rats. On the basis of animal bioassay data, the chronic inhalation DMEL for the risk of cancer in workers would be derived as 0.13 mg/m3(0.04 ppm). Studies on the in vitro metabolism of chloroprene (Cottrell et al, 2001; Munter et al 2003 and Himmelstein et al 2004) show marked differences in metabolism across species with the mouse being at considerably more risk for toxicity. Although the full mechanism leading to tumor development in the lung or other tissues is not completely understood, chloroprene metabolism, specifically its greater oxidation leading to epoxides or other reactive metabolites, slower epoxide hydrolysis, and the potential for glutathione depletion in the mouse relative to other species indicates that the mouse is not an appropriate model for human health risk assessment. Species differences in tumor outcome are also supported by the lack of lung and liver tumours in other rodent species where observed activation:detoxication ratios are lower than for mice e.g. Wistar rat and Syrian Golden hamster (Trochimowicz et al., 1998). This lack of species similarity in response is also seen in the outcome of the latest human epidemiology studies were no significant increase in lung or liver cancer deaths were reported (Marsh et al. 2007). 

Collectively, these data show that the mouse is not a good predictor for human outcome. While quantitative response factors cannot be derived with certainty, intrinsic clearance values for lung and liver address species and tissue specific concerns for sensitivity. The comparison of mouse to human activation:detoxication ratios suggests that a reduced sensitivity of at least 10 for liver effects and at least 100 for lung effects in the mouse relative to humans. On this basis, the application of an overall assessment factor of 30 to the adjusted BMDL10%is expected to provide a conservative margin of safety towards potential effects in humans.

Taking into consideration the expected species differences in the metabolism of chloroprene and the availability of more relevant human data, the human DNEL/DNEL for chronic, systemic effects derived in the previous section is proposed for risk assessment purposes.

Table X: DMEL values for workers following working-life inhalation exposures to chloroprene derived from tumour incidences observed in the NTP (1998) 2-year bioassays using the large assessment factor approach.

 

 

 

Large assessment factor approach

Site

Tumour

Species (sex)

Best-fit model

BMDL10%(mg/m3)a

DMELb(mg/m3)

All

Hemangioma/hemangiosarcoma

Mouse (f)

Log-logistic

84

2.80

All

Hemangioma/hemangiosarcoma

Mouse (m)

Multi-stage

12

0.40

Lung

Aveolar/bronchiolar adenoma or carcinoma

Mouse (f)

Log-logistic

4

0.13

Lung

Aveolar/bronchior adenoma or carcinoma

Mouse (m)

Log-logistic

5

0.16

Lung

Aveolar/bronchior adenoma or carcinoma

Rat (m)

Multi-stage

162

5.4

Mammary

Adenocarcinoma, carcinoma

Mouse (f)

Multi-stage

31

1.03

Mammary

Adenocarcinoma, carcinoma

Rat (f)

Multi-stage

8

0.26

Harderian gland

Adenoma or carcinoma

Mouse (f)

Gamma

125

4.17

Harderian gland

Adenoma or carcinoma

Mouse (f)

Log-logistic

101

3.36

Kidney

Renal tubule adenomas or carcinomas

Mouse (m)

Log-logistic

101

3.36

Oral cavity

(papillomas or carcinomas)

Rat (f)

Log-logistic

75

2.50

Oral cavity

(papillomas or carcinomas)

Rat (m)

Gamma

89

2.97

Thyroid

Follicular cell adenomas or carcinomas

Rat (m)

Log-logistic

227

7.57

Thyroid

Follicular cell adenomas or carcinomas

Rat (f)

Multi-stage

68

2.27

Liver

Hepatocellular adenoma or carcinoma

Mouse (f)

Gamma

53

1.78

aPOD adjusted for working life exposures and light exercise

bTotal assessment factor applied: 30

 

Dermal route

The critical effect of dermal exposure to chloroprene is skin irritation, for which a threshold has not been identified. Prolonged, dermal contact cannot be tolerated. Occupational exposures to chloroprene should be controlled by the use of appropriate personal protective equipment and good industrial hygiene to prevent skin irritation. A long-term DNEL for systemic effects following dermal exposures is not therefore derived.

Systemic effects (non-cancer)

Long-term studies in animals indicate that non-cancer, systemic effects (including hepatotoxicity and hematological changes) following repeated inhalation exposures are seen at higher doses than those associated with nasal (local) degenerative changes. The chronic DNEL for local effects is therefore considered to be protective towards any systemic non-cancer effects.

Acute effects

Local effects

Inhalation route

Local effects have not been reported in 4 hour inhalation studies in animals. In repeated dose studies (e.g. 16 day, 13 week and 2 year studies carried out by NTP, 1998), the critical local effect in rodents following inhalation exposure to chloroprene was respiratory tract irritation based on degeneration of the nasal olfactory epithelium. In a 16-day rodent study, the lowest effect level for olfactory degeneration was 32 ppm (the lowest dose in the study) and a NOAEC was not identified in this study. Whilst a NOAEC of 12 ppm for olfactory degeneration was identified in a 13 week inhalation study in rats, a LOAEC of 12.8 ppm (the lowest dose tested was reported ina two year inhalation study.

Since all these studies involved repeated administration of chloroprene, and their relevance for informing the derivation of threshold for irritation effects following acute, transient exposure is not clear, an acute DNEL for local effects has been derived as follows:

According to German technical rules (TRGS 900) maximum peak occupational exposures can be derived from chronic exposure limits by the application of an additional assessment factor (typically a factor of 8). Short-term exposures which exceed the chronic exposure limit by 8 -fold for more than four times in a working shift for periods of more than 15 minutes are not regarded as acceptable and would result in the exceedance of the long-term occupational limit (TRGS-900; 2006; modified and supplement in 2010).

an acute inhalation DNEL for local effects in workers based on the TRGS-900 approach is proposed:

8 x 0.8 mg/m3 (chronic DNEL for local effects) = 6.4 mg/m3

An acute inhalation DNEL of 6.4 mg/m3 (1.96 ppm) is proposed for local respiratory effects in workers.

Systemic effects

Inhalation

Acute (4 hour) inhalation exposures to chloroprene at doses > 160 ppm in rodents have been associated with signs of hepatic toxicity. In 16-day inhalation studies in rodents, the NOAEL of 12 ppm (43.3 mg/m3) was identified based on observations of significantly decreased bodyweights at consecutively higher doses.

Since all these studies involved repeated administration of chloroprene, and their relevance for informing the derivation of threshold for acute systemic effects following acute, transient exposures is not clear, an acute DNEL for systemic effects has been derived as follows:

According to German technical rules (TRGS 900) maximum peak occupational exposures can be derived from chronic exposure limits by the application of an addtional assessment factor (typically a factor of 8). Short-term exposures which exceed the chronic exposure limit by 8 -fold for more than four times in a working shift for periods of more than 15 minutes are not regarded as acceptable and would result in the exceedance of the long-term occupational limit (TRGS-900; 2006; modified and supplement in 2010).

An acute inhalation DNEL for systemic effects in workers based on the TRGS-900 approach is proposed to be:

8 x 0.8 mg/m3 (chronic overall DNEL) = 6.4 mg/m3

An acute inhalation DNEL of 6.4 mg/m3 (1.96 ppm) is proposed for systemic effects in workers.

Dermal route

The critical effect of dermal exposure to chloroprene is skin irritation, for which a threshold has not been identified. Occupational exposures to chloroprene should be controlled by the use of appropriate personal protective equipment and good industrial hygiene to prevent skin irritation. Acute DNELs for systemic effects following dermal exposures are not therefore derived.

 

References

Batke M, Escher S, Bitsch, A and Mangelsdorf, I (2010) Evaluation of risk assessment factor for interspecies and time extrapolation Fraunhofer Institute for Toxicology and Experimental Medicine -ITEM, Hannover, Germany

Bukowski, J. A., 2009. Epidemiologic evidence for chloroprene carcinogenicity: Review of study quality and its application to risk assessment. Risk Analysis. 29, 1203-1216.

ECETOC (2003) Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium.

ECETOC (2010) Guidance on Assessment Factors to Derive DNELs. Technical Report No. XXX. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium (to be published soon)

Himmelstein MW, Carpenter SC, Hinderliter PM, Snow TA and Valentine R (2001). The metabolism of beta-chloroprene: preliminary in vitro studies using liver microsomes.Chem Biol Inter 135-136, p267-284

Le HQ and Symons JM (2010). Derivation of a No adverse-Effect Level from an epidemiologic study of occupational chloroprene exposure and respiratory system cancer mortality. DuPont Haskell Globel Centers for Health and Environmental Sciences. RA-09092010-HQL.

Marsh, G. M., et al., 2007a. Mortality patterns among industrial workers exposed to chloroprene and other substances: I. General mortality patterns. Chemico-Biological Interactions. 166, 285-300.

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Melnick, R. L., et al., 1999. Multiple organ carcinogenicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344/N rats and B6C3F1 mice and comparison of dose-response with 1,3-butadiene in mice. Carcinogenesis. 20, 867-878.

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[1]REACH, Chapter R.7a: Endpoint specific guidance

[2]As the assessment factors to be considered are the same for the DNEL and DMEL derivation, it is assumed that the derived DMEL would be the same as the DNEL.

General Population - Hazard via inhalation route

Systemic effects

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

Justification for no DNEL/DMEL derivation for the general public:

Chloroprene is used for the manufacture of high molecular polymers only. The residual monomer in the polymers is below the detection limits of 1 ppm. The not detectable residual monomer, if any is present, is securely encapsulated in the polymer matrix. Therefore exposure to residual monomers is certain unlikely.