Chloroform

Toxicological Summary

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

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: German MAK Commission

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEC

Value:

25 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: German MAK Commission: value for short-term exposure (15 minutes)

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

DNEL derivation method:

other: German MAK Commission

Overall assessment factor (AF):

10

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

DNEL derivation method:

other: German MAK Commission: value for short-term exposure (15 minutes)

Justification:

Accepted AF for workers

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.86 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

52.5

Dose descriptor starting point:

LOAEL

Value:

15 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Studies on dermal exposure to chloroform are not available.

AF for dose response relationship:

3

Justification:

AF = 3 for use of LOAEL

AF for other interspecies differences:

3.5

AF for intraspecies differences:

5

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:

low hazard (no threshold derived)

Additional information - workers

DNEL for short-term occupational inhalation exposure:

The German MAK Commission has established a short-term inhalation exposure limit value of 5 mg/m3 for 15 minutes exposure duration. This value is used as the DNEL for 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 considered 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. 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. For chloroform a SCOEL-derived value (10 mg/m3) dates from 1995, but new toxicological studies are available from that date. In addition, 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. Because the MAK value is set at a later date taking into account more recent information, it is proposed to the use the German MAK value (2.5 mg/m3) instead of deriving a DNEL. The MAK value is the lowest occupational exposure level in Europe, and is based on available and relevant toxicity data at present. Although the MAK documentation dates from 1999, it should be noted that the last substantiation statement of the MAK Commission dates from October 2002 (status of May 2002). However, there is only limited new information regarding toxicological effects on animals available except 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. 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, at the dose-levels tested. This implies a threshold for the carcinogenicity of chloroform. The derived long-term DNEL (2.5 mg/m3) will protect workers against effects of chloroform on the liver and the kidney and thus against the development of kidney or liver cancer. Since chloroform is not classified for effects on fertility and since the potential developmental effects appear at concentrations higher than the NOAEC for long-term systemic toxicity and carcinogenicity (50 mg/m3 versus 25 mg/m3), the long term DNEL will protect workers from the possible effects of chloroform on reproduction.

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.

 

Worker, DNEL for long-term occupational dermal exposure:

Studies on dermal repeated exposure to chloroform are not available. The oral repeated dose toxicity study has been 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.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.625 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: Derived from the DNEL long-term for workers (MAK value) which is 2.5 mg/3

Overall assessment factor (AF):

4

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.625 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: Derived from the DNEL long-term for workers (MAK value) which is 2.5 mg/3

Overall assessment factor (AF):

4

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

DNEL related information

Explanation for the modification of the dose descriptor starting point:

Studies on dermal exposure to chloroform are not available. Moreover, chloroform is only used in industrial processes.

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)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.33 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

175

Modified dose descriptor starting point:

NOAEL

Value:

57.5 mg/kg bw/day

AF for interspecies differences (allometric scaling):

7.5

AF for other interspecies differences:

2

AF for intraspecies differences:

10

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

 DNEL for long-term inhalation exposure of the general population:

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 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.

 

The starting point for deriving the DNEL for the general population is the DNEL for workers which is based on the MAK value of 2.5 mg/m3. A total assessment factor (AF) of 4 is applied on this value: a factor 2 to extrapolate from workers (interspecies factor 5) to the general population (interspecies factor 10), and a factor of 2 to correct for duration (exposure of workers 8 h/day – 10 m3 breathing volume versus the general population 24 h/day – 20 m3 breathing volume). This results in a DNEL (inhalation long-term, systemic and local effects) of 0.625 mg/m3.