Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
333 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.94 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
88
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

DNEL for short-term occupational inhalation exposure:

The available human data indicate that humans exposed for 30 minutes to chloroform vapours at a concentration of 3330 mg/m3 did not suffer from adverse effects; only a strong odour was perceived (Lehmann and Hasegawa, 1910 in ACGIH interim report 2007). This concentration is recognised as a reasonable NOAEC for systemic effects due to short-term inhalation exposure. The DNEL can be determined from this vapour concentration by applying a factor of 5 for intraspecies differences and a factor of 2 for remaining uncertainly (old study) resulting in a DNEL value of 333 mg/m3.

However, it should be worthy to note that a short-term inhalation exposure limit value of 10 mg/m3 has been established in Germany for 15 minutes exposure duration. In some situations, it should be more appropriate to consider the short-term occupational exposure of workers.

DNEL for short-term occupational dermal exposure:

In accordance with the EU risk assessment report for chloroform (France 2007) it is concluded that occupational dermal exposure to irritating concentrations of chloroform is not a risk for workers. The following statement is found on page 139 of the draft human report of this EU risk assessment: “Dermal exposure to irritating concentrations of chloroform is considered to occur only accidentally if the required protection is strictly adhered to. It is assumed that existing controls (i.e., engineering controls and personal protective equipment based on classification and labelling with R38) are applied. Therefore, it is concluded that chloroform is of no concern for workers with regard to effects as a result of dermal exposure for scenarios 1 and 2 in which irritating concentrations of chloroform are handled (conclusion ii).” It is therefore suggested not to derive a DNEL for dermal local effects of chloroform.

DNEL for long-term occupational inhalation exposure:

As authorized by the ECHA guidance, an Indicative European Occupational Exposure Limit (IOEL) value could be used in place of the derivation of a DNEL, unless new available scientific information does not support the use of this IOEL. Nevertheless, concerning chloroform, the SCOEL value (10 mg/m3) dates from 1995, and new toxicological studies are available from that date. Therefore the SCOEL value should not be used in place of the derivation of DNELs for workers. However, in the same approach, the ECHA guidance authorizes a registrant to use a national OEL in place of deriving a DNEL in case where toxicological information and evaluations of health effects used for setting the national OEL are documented and available. Therefore, it is proposed to use the German MAK value (2.5 mg/m3) in place of the derivation of the DNEL. This MAK value is the lowest occupational exposure level in Europe, and is based on available and relevant toxicological data at present. Even the MAK documentation dates from 1999, it should be noted that the last substantiation statement of the so-called MAK Commission dates from October 2002 (status of May 2002) and is based essentially on the previous MAK paper of 1999. There is no new toxicological information regarding toxicological effects on animals, excepting the publication of Yamamoto et al. (2002), which provides a NOAEC of 25 mg/m3 for carcinogenic effects (same value as NOAEC for long-term, systemic effects in the study of Templin et al., 1996). The Yamamoto study is actually the same as the Nagano study (1998) with more details. The MAK value (2.5 mg/m3) is based on cell proliferation in the liver and in the kidney in the rat (after inhalation of chloroform for 13 weeks, NOAEC is 25 mg/m3- Templin et al., 1996). The MAK value was established to be representative of 8 hours of inhalation exposure occurring during a full working shift. These are the relevant exposure conditions for workers under normal conditions.

The studies in animals revealed that chloroform could cause an increased incidence of kidney tumours in male rats or mice and an increased incidence of liver tumours in mice of either sex. These induced tumour responses are postulated to be secondary to sustained or repeated cytotoxicity and secondary regenerative hyperplasia, according to the dose-levels tested. The observance of the long-term DNEL will avoid the emergence of cell proliferation in the liver and in the kidney and thus the development of cancer. Consequently, it is not proposed to derive a DNEL for carcinogenic effects.

Since chloroform is not classified for its effects on fertility and since the potential developmental effects appear with doses higher than the long-term systemic and carcinogenic NOAECs (50 mg/m3 versus 25 mg/m3), it is not proposed to derive a DNEL for reproductive or developmental effects as the observance of the long term DNEL will protect workers from the possible effects of chloroform on the reproduction.

Cell proliferation was observed in the nose (ethmoid region) of male F-344 rats following inhalation exposure to 10 mg/m3 for 6 h/day for 4 days, however, at an exposure level of 50 mg/m3 and under similar exposure conditions only minimal to mild lesions were seen and the effects were transient (Templin et al. 1996b). A late atrophy was present in the areas of early cell proliferation and in the whole ethmoid region of the nasal cavity after 13 weeks of exposure. The atrophy was minimal at exposure levels of 10 mg/m3 and more distinct at higher exposure concentrations of 50 mg/m3 or greater. Following exposure to 50 mg/m3 for 6 h/day for 7 consecutive days, male F-344 rats had lesions in nasal turbinates, including increased cell proliferation in central, proximal, and distal regions of the first endoturbinate, and histological changes in the central turbinate bone (Larson et al. 1994a; Méry et al. 1994). Cell proliferation was also seen in the nasal turbinates of female B6C3F1 mice exposed at 10 mg/m but not at 1.5 mg/m3, for 6 h/day, 7 days/week, for 3 weeks (Larson et al., 1996). Increased cell proliferation was detected in the first endoturbinate of the nasal passage in female B6C3F1 mice exposed to 50 mg chloroform/m3, 6 h/day, for 7 consecutive days (Méry et al., 1994) but no microscopic damage was seen in the nasal passages of female B6C3F1 mice exposed to up to 1500 mg/m3 for 6 h/day for 7 consecutive days. Thus, it appears that the notable effects of chloroform on the respiratory tract occur with doses higher than the long-term systemic and carcinogenic NOAECs (50 mg/m3 versus 25 mg/m3). Therefore, it is not proposed to derive a DNEL for effects on respiratory tract as the observance.

In conclusion:

The DNEL for long-term occupational inhalation exposure is 2.5 mg/m3. This value is considered to protect workers from the possible local, systemic, reproductive or carcinogenic effects of chloroform.

DNEL for long-term occupational dermal exposure:

Although the risk management measures that are in place are protecting the workers from dermal contact with the substance, an eventual reasonable misuse has to be taken into account.

Worker, dermal – repeated dose systemic and carcinogenicity toxicity:

Studies on dermal repeated exposure to chloroform are unavailable. The repeated inhalation NOAEC of 25 mg/m3 will be used to derive the dermal threshold value and route-to-route extrapolation is performed (Templin et al. 1998). The absorption efficiencies for chloroform are given in the EU risk assessment (France 2007): 80 % via inhalation route and 10 % via dermal route. The inhalation volume of the testing animals (mouse: 0.41 m3/kg for the six hours, France 2007) is taken into account. There is no extrapolation from subchronic to chronic effects because comparable effect levels were seen at both exposure durations. The inhalation NOAEC can thus be corrected to produce a dermal NOAEL: 25 * 0.41 * 0.8 / 0.1 = 82 mg/kg bw/day. The assessment factors applied in the calculation of the DNEL are 7 (difference between mouse and human), 2.5 (remaining interspecies differences) and 5 (intraspecies differences). The DNEL thus is 82 / (2.5 * 5 * 7) = 0.94 mg/kg bw/day or 65.8 mg/person/day.

Alternatively, an oral study may be used to derive a dermal threshold value. The repeated oral LOAEL of 15 mg/m3 from a study in dogs is used for the derivation (Heywood et al. 1979), and absorption in the gastrointestinal tract is 100 % and dermal absorption is 10 %. The corrected LOAEL is 15 * 100 / 10 = 150 mg/kg bw/day. The assessment factors are 3 (use of LOAEL), 2.5 * 1.4 (interspecies differences) and 5 (intraspecies differences). The DNEL thus is 150 / (3 * 2.5 * 1.4 * 5) = 2.86 mg/kg bw/day or 200.2 mg/person/day. As this DNEL is considerably higher than the DNEL derived from the inhalation repeated dose toxicity data, it will not be considered further.

Worker, dermal – repeated dose reproductive toxicity (toxicity on fertility):

Chloroform is not classified for its effects on fertility. The effects observed on fertility (i.e. slight increase in relative epididymis weight in the F1 generation and minimal epididymal lesions in the F0 generation; Chapin et al. 1997) are minimal. . The EU risk assessment (France 2007) suggests the derivation of a DNEL from an oral reproductive toxicity study giving a NOAEL of 16 mg/kg/day (Chapin et al. 1997). The corrected NOAEL for dermal toxicity is calculated as 160 mg/kg/day (France 2007). The assessment factors that are suggested in the EU risk assessment are 7 (differences between mouse and humans), 2.5 (remaining interspecies differences) and 5 (intraspecies differences). The eventual DNEL thus calculated is 160 / (7 * 2.5 * 5) = 1.83 mg/kg/day or 1.83 * 60 = 109.8 mg/person/day. Based on the above-mentioned arguments and since the observance of dermal repeated dose systemic/carcinogenicity DNEL will protect the workers from these effects, it is therefore not proposed to derive a dermal DNEL for the possible effects of chloroform on fertility.

Worker, dermal – repeated dose developmental toxicity:

A classification of chloroform for reproductive toxicity, category 3 (R63: possible risk of harm to the unborn child) has been proposed by the French rapporteur in the REACH Annex XV dossier (France 2008). The EU risk assessment (France 2007) suggests the derivation of a DNEL from an inhalation developmental toxicity study giving a NOAEL of 50 mg/m3 (Baeder and Hofmann 1991). The dermal NOAEC calculated in the EU risk assessment is 50 * 0.34 * 0.8 / 0.1 = 136 mg/kg bw/day. The assessment factors that are suggested in the EU risk assessment are 4 (differences between rat and humans), 2.5 (remaining interspecies differences) and 5 (intraspecies differences). The DNEL thus calculated is 136/ (4 * 2.5 * 5) = 2.72 mg/kg bw/day or 2.72 * 60 = 163.2 mg/person/day.

It is worth to note that the observance of the dermal repeated dose systemic/carcinogenicity DNEL will protect the workers from the possible effects of chloroform on the development of the unborn child.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.18 mg/m³
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
25
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

DNEL for long-term inhalation exposure of the general public

The use of chloroform in products available to the general public is strictly regulated by European law and concentrations of chloroform in such products must not exceed 0.1 %. The use of retail products thus will not cause direct contact of consumers with chloroform. The identified uses of the substance described in the present document will not lead to direct consumer contact with chloroform either. Only indirect consumer contact with chloroform is anticipated. The gross majority of chloroform released to the environment will partition into the atmosphere. The important route of indirect consumer exposure to chloroform therefore is via inhalation. A DNEL for repeated-dose systemic inhalation toxicity is derived for the general public.

Consumer, inhalation – repeated dose systemic toxicity:

The starting point is the NOAEC of 25 mg/m3 for renal toxicity, cell replication proliferation and renal tumour formation found in a sub-chronic 90-day study performed in mice (Templin et al. 1998). The corrected starting point is obtained by correcting for the exposure conditions (6 hours/24 hours) and for the duration of exposure (5 days/7 days). The corrected NOAEC is 4.5 mg/m3. The assessment factors are 2.5 (remaining interspecies differences) and 10 (intraspecies differences). No assessment factor for extrapolation from sub-crhonic to chronic is used since effects are not dependant on exposure duration. The DNEL thus is 4.5 / (2.5 * 10) = 0.18 mg/m3.

This value is clearly below the value established for long-term repeated dose inhalation exposure of workers. However, it has to be realised that consumers experience longer exposure duration. In addition, the variability in health status and overall susceptibility to chemical exposure are much greater in the general public compared to workers.