chloromethane; methyl chloride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.5 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

156 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAECinhalatory*(6 h/d / 8 h/d)*(6.7 m³ (8h)/10 m³ (8h))=150 ppm*(6 h/d / 8 h/d)*(6.7 m³ (8h)/10 m³ (8h))=75 ppm = 156 mg/m³

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEC.

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

5

Justification:

Default AF for workers

AF for the quality of the whole database:

1

Justification:

DNEL is based on a high-quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Additional information - workers

Workers might be exposed to chloromethane during manufacture, processing or filling in appropriate containers by the inhalative route. Exposure of skin is not regarded as relevant due to the physical-chemical properties (see exposure section).

With regard to the Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health (publ. May 2008) a national occupational exposure limit (OEL) which is based on a scientific evaluation was used as DNEL at first dossier submission in 2010. In 1992 the German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) derived an OEL for the MAK category 3B carcinogen chloromethane of 50 ppm (100 mg/m³, MAK value) based on the results of animal experiments and workplace observations (The German MAK Commission classifies a substance into category 3B for carcinogenicity, if there is some evidence for a carcinogenic action from in vitro tests and animal experiments, but it is not sufficient for classification into another category.). The value was reconfirmed in 2001 and was adopted without modifications in national German list of limit values (TRGS 900) in 2006.

Based on the CoRAP decision regarding risk assessment members of the Methyl chloride REACh consortium sought advice from an independent expert (Prof. Dekant) firstly on the question, if the German OEL-value (MAK) for chloromethane is equivalent to a DNEL within the REACH-framework and secondly to intensify the discussion on the relevance of the carcinogenicity data for the workplace exposure and therefore for DNEL/DMEL derivation.

Based on the expert statement provided by Dekant and Colnot (2013), the German national OEL value based on the conclusions of the MAK commission cannot be considered equivalent to a DNEL. There are methodological differences in the approach used in deriving MAK OELs and DNELs, the current MAK OEL value of 50 ppm is not derived from the most recent toxicological studies, and potential damage to the embryo or fetus cannot be excluded even when the MAK value is observed. Thus, the MAK OEL of 50 ppm cannot be carried forward to a risk assessment according to REACH (Dekant and Colnot, 2013).

The basis for the consortiums decision to proceed with DNELs instead of DMELs for risk assessment is the following conclusion by Dekant (2015) on the mode of action for renal tumor formation.

The available information indicates that the tumor induction in the kidneys observed in male mice in a 2-year inhalation carcinogenicity study with mice and rats is due to a species-specific mode of action. This mode of action involved oxidation of chloromethane to formaldehyde by a specific cytochrome P450 enzyme only expressed in the renal cortex of male mice, but not in female mice, rats, and humans. After prolonged inhalation of high concentrations of chloromethane, excess formaldehyde formed in the kidney of the male mouse results in cytotoxicity, compensatory cell proliferation, and, finally tumors. This mode of action does not have relevance to humans since such a cytochrome P450 enzyme is absent in human kidney samples. In the absence of this cytochrome P450 enzyme, conjugation with glutathione is the major pathway of chloromethane. Moreover, the mode of action has a dose response with a clear threshold since kidney damage and compensatory cell proliferation is required and formaldehyde is endogenously formed as a normal intermediate in biosynthetic processes. Thus, even when formed, small additional amounts of formaldehyde derived from the bioactivation of chloromethane in humans, can be efficiently detoxified (Dekant 2015).

Overall, Dekant and Colnot (2013) concluded, that tumor formation, reproductive effects and systemic toxicities observed after exposure to chloromethane are considered as thresholded effects. Thus, all critical effects related to chloromethane toxicity are threshold‐based and permit the derivation of classical DNEL‐values within the REACH framework. Based on available data, endocrine disruption as a mode of action can be excluded (Dekant and Colnot, 2013). For more details please refer to the Section Genotoxicity, Carcinogenicity and to the expert review by Dekant (2015) attached in IUCLID Section 13.

SCOEL (2017) concludes that an experimentally derived NOAEC of 150 ppm chloromethane is a valid point of departure for deriving an OEL and that there is no indication of a genotoxic or carcinogenic effect at this dose level or below. The recommended 8-hour TWA is 20 ppm (42 mg/m3). Although, for practical reasons, this recommended value is not used for the risk assessment it demonstrates the conservativeness of derived DNELs and the corresponding risk estimates.

Based on a CoRAP decision on Chloromethane, a prenatal developmental toxicity study in a non-rodent species was performed via the inhalation route (Theuns-van Vliet, 2016). In accordance with OECD 414 and under GLP conditions, pregnant rabbits were exposed to Chloromethane at the concentrations of 250, 500 and 1000 ppm (equivalent to 546, 1053 and 2086 mg/m³) for 6 h/day during gestation day 6 to 28. The NOAEC for developmental toxicity and teratogenicity was considered to be ≥ 1012 ppm (equivalent to 2086 mg/m³).

Taking into account all available data on Chloromethane, the NOAEC of 150 ppm (equivalent to 310 mg/m³) from a two‐generation toxicity study in rats was used as most sensitive value for the DNEL derivation (Hamm et al., 1985). The first step in deriving a DNEL is to correct the rodent NOAEC after inhalation for the differences between experimental (6 h/day) and human occupational exposure conditions (8 h/day) considering the time adjusted human respiratory volume at light activity:

NOAECcorr = NOAECinhalatory * (6 h/d / 8 h/d) * (6.7 m³ (8h) / 10 m³ (8h))

This calculation gives a corrected NOAEC of 75 ppm (156 mg/m³).

Based on ECHA guidance, the next step in the calculation of the DNEL is to address uncertainties in the extrapolation of experimental data to the human exposure situation, taking into account variability and uncertainty.

A factor to allow for allometric scaling is not required since a concentration expressed in ppm is already scaled according to the allometric principle since ventilation rate depends on the basal metabolic rate. However, according to ECHA (2012) an additional default factor of 2.5 for toxicodynamic interspecies differences not related to metabolic rate has to be included. Although this factor has been criticized based on statistical reasons (ECETOC, 2010), the inclusion of this additional factor is maintained as it is not known if humans differ in their capacity to detoxify metabolites like methanethiol, and how much that detoxification capacity might vary.

AF (interspecies factor) = 2.5

For workers, as standard procedure for threshold effects, a default assessment factor of 5 has to be used.

AF (intraspecies factor) = 5

In order to derive the systemic DNEL, the overall AF is to be applied directly to the corrected dose descriptor (NOAECcorrected of 75 ppm):

DNELsystemic worker = NOAECcorrected / (AF(inter) x AF(intra)) = 75/(2.5 x 5) =6 ppm = 12.5 mg/m³

 

Reference:

Deutsche Forschungsgemeinschaft (DFG): Gesundheitsschädliche Arbeitsstoffe – Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten.Chloromethan. Weinheim: WILEY-VCH (1984, 1992, 2001)

Deutsche Forschungsgemeinschaft (2015) Überprüfung von Stoffen im MAK-Werte- und BAT-Werte-Teil, in MAK- und BAT-Werte-Liste 2015, Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim, Germany. doi: 10.1002/9783527694983.app4

Dekant, W. and Colnot, T. (2013) Expert Review: Can the German OEL-value (MAK) for Chloromethane (MeCl) be considered to be equivalent to a DNEL within the REACH-framework?

Dekant, W. (2015) Expert Review: Additional comments on mutagenicity and carcinogenicity of chloromethane: Human relevance of male mouse-specific renal tumors

SCOEL, Scientific Committee on Occupational Exposure Limits (2017), REC-191 - Chloromethane, Publications Office of the European Union, Luxembourg, ISBN: 978-92-79-66616-2

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Since exposure of the general public is not relevant, DNELs for the general population were not derived.