2-chloroacetamide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.705 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

17.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key 90-day oral toxicity study available; no repeated dose inhalation toxicity study available.

AF for dose response relationship:

1

Justification:

96% bioavailability after oral administration (is already maximal)

AF for differences in duration of exposure:

2

Justification:

ECHA default for subchronic studies

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling already applied in route-to-route extrapolation

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No other uncertainties

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.3 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

141 ng/m³

Explanation for the modification of the dose descriptor starting point:

Key acute oral toxicity study available; no acute inhalation toxicity study available.

AF for dose response relationship:

1

Justification:

Various doses available; dose without effects considered as NOAEL/NOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling already applied in route-to-route extrapolation

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No other uncertainties

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)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.171 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):

100

Modified dose descriptor starting point:

NOAEL

Value:

17.1 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Key oral repeated dose toxicity study contained all necessary toxicological parameters (in contrast to dermal repeated dose toxicity study).

AF for dose response relationship:

1

Justification:

Various doses available; NOAEL clearly defined

AF for differences in duration of exposure:

2

Justification:

ECHA default for subchronic studies

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No other uncertainties

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:

0.012 mg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor:

other: NOAEL

AF for dose response relationship:

1

Justification:

Various doses available; NOAEL clearly defined

AF for differences in duration of exposure:

2

Justification:

ECHA default for subchronic studies

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable for local effects

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No other uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Sources and info for the DNEL calculations:

In a key oral acute toxicity study in female rats dosed at 80, 125, 160, 200 and 320 mg/kg bw, Chloroacetamide had an LD50 of 138 mg/kg bw (Hoechst, 1976). Deadly poisoned animals (125, 160, 200 and 320 mg/kg bw) showed impaired balance, gasping breathing and bended posture; no macroscopically effects were observed. 80 m/kg bw was considered as NOAEL.

In a key 90 day oral repeated dose study (Hoechst, 1985) 80 Wistar rats (40 males and 40 females) were administered at doses of 0, 20, 100 and 500 mg Chloroacetamide/kg feed /day (equivalent to 0, 2, 10 and 50 mg/kg bw/day). In the high dose group, reduced body weight gain/food consumption and increased leucocytes were observed, as well as decreased liver weights in females, and smaller testes, reduced testicular weights, proliferation of Leydig cells and depression - standstill of spermiogenesis in males. After a 29 -day recovery period, partial to complete regeneration was observed in the testis, therefore this was considered to be reversible. The NOAEL was 100 mg/kg feed, corresponding with 10 mg/kg bw/day.

In a 30 day dermal repeated dose toxicity (Hoechst, 1967) Chloroacetamide was tested without coverage in female rabbits at 25, 50, 100, 200 and 400 mg/kg bw /day (0.063, 0.13, 1.25, 0.50, 1.00 mL/kg bw/day). After the end of testing all surviving animals were observed for 3 days. In the 25 and 50 mg dose groups there were no findings. In the 100 mg dose group a slight body weight loss was observed during treatment and histological changes in liver, heart muscle and spleen. In the 200 mg dose group similar observations were done with a more significant weight loss. In the 400 mg dose group 3 animals died (1 on day 1, 2 and 3 respectively). Similar changes as in the 100 and 200 mg dose groups in liver, heart muscle and spleen were observed and a significant weight loss. In all dose groups there were local changes of the treated skin area (encrustation to induration). The dermal NOAEL was 50 mg/kg bw/day.

In a 13 weeks dermal toxicity repeated dose study, Konservierungsmittel CA 24 was applied to the shaved backs of male adult Wistar-rats, at doses of 12.5 and 50.0 mg/kg in Lanette (1 or 2%) or Aqua dest (2%). Neither test dependent or substance specific changes were observed in the growth parameters and histomorphological examinations. The dermal “no-effect” level of CA 24 in male adult rats is 50 mg/kg bw.Taking into account the 70% Chloroacetamide content and assuming that sodium benzoate was inactive on the skin, 35 mg act./kg bw was considered as local NOAEL. Based on the lower NOAEL, this was considered as key study. Considering a mean body weight of 300 g (based on study data) and a surface area of 325 cm2 (Derelanko, 2008; The Toxicologist's Pocket handbook p29), 10.5 mg was applied on 32.5 cm2 (10% body surface), corresponding to 0.32 mg/cm2. Compared to the rabbit NOAEL of 50 mg/kg bw and a mean body weight of 2.5 kg (based on study data) and a surface area of 1270 cm2 (Derelanko, 2008; The Toxicologist's Pocket handbook p29), 125 mg was applied on 127 cm2 (10% body surface), corresponding to 0.98 mg/cm2. Therefore the rat value was considered most conservative.

As the key 3-month dermal study (IBR, 1971; NOAEL = 50 mg/kg bw) did not have biochemistry and full histopathology, the NOAEL from the 90-day oral study was used as most conservative. In a key 90 day oral repeated dose study (Hoechst, 1985) 80 Wistar rats (40 males and 40 females) were administered at doses of 0, 20, 100 and 500 mg Chloroacetamide/kg feed /day (equivalent to 0, 2, 10 and 50 mg/kg bw/day). In the high dose group, reduced body weight gain/food consumption and increased leucocytes were observed, as well as decreased liver weights in females, and smaller testes, reduced testicular weights, proliferation of Leydig cells and depression - standstill of spermiogenesis in males. After a 29 -day recovery period, partial to complete regeneration was observed in the testis, therefore this was considered to be reversible. The NOAEL was 100 mg/kg feed, corresponding with 10 mg/kg bw/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.174 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Value:

8.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key 90-day oral toxicity study available; no repeated dose inhalation toxicity study available.

AF for dose response relationship:

1

Justification:

96% bioavailability after oral administration (is already maximal)

AF for differences in duration of exposure:

2

Justification:

ECHA default for subchronic studies

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling already applied in route-to-route extrapolation

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No other uncertainties

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.78 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

69.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key acute oral toxicity study available; no acute inhalation toxicity study available.

AF for dose response relationship:

1

Justification:

Various doses available; dose without effects considered as NOAEL/NOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling already applied in route-to-route extrapolation

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No other uncertainties

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)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.086 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):

200

Modified dose descriptor starting point:

NOAEL

Explanation for the modification of the dose descriptor starting point:

Key oral repeated dose toxicity study contained all necessary toxicological parameters (in contrast to dermal repeated dose toxicity study).

AF for dose response relationship:

1

Justification:

Various doses available; NOAEL clearly defined

AF for differences in duration of exposure:

2

Justification:

ECHA default for subchronic studies

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No other uncertainties

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:

0.006 mg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor:

other: NOAEL

AF for dose response relationship:

1

Justification:

Various doses available; NOAEL clearly defined

AF for differences in duration of exposure:

2

Justification:

ECHA default for subchronic studies

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No other uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 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):

200

Modified dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Key 90-day oral repated dose toxicity study available

AF for dose response relationship:

1

Justification:

Various doses available; NOAEL clearly defined

AF for differences in duration of exposure:

2

Justification:

ECHA default for subchronic studies

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No other uncertainties

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.8 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

80 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Various doses available; NOAEL clearly defined

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No other uncertainties

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Sources and info for the DNEL calculations:

In a key oral acute toxicity study in female rats dosed at 80, 125, 160, 200 and 320 mg/kg bw, Chloroacetamide had an LD50 of 138 mg/kg bw (Hoechst, 1976). Deadly poisoned animals (125, 160, 200 and 320 mg/kg bw) showed impaired balance, gasping breathing and bended posture; no macroscopically effects were observed. 80 m/kg bw was considered as NOAEL.

In a key 90 day oral repeated dose study (Hoechst, 1985) 80 Wistar rats (40 males and 40 females) were administered at doses of 0, 20, 100 and 500 mg Chloroacetamide/kg feed /day (equivalent to 0, 2, 10 and 50 mg/kg bw/day). In the high dose group, reduced body weight gain/food consumption and increased leucocytes were observed, as well as decreased liver weights in females, and smaller testes, reduced testicular weights, proliferation of Leydig cells and depression - standstill of spermiogenesis in males. After a 29 -day recovery period, partial to complete regeneration was observed in the testis, therefore this was considered to be reversible. The NOAEL was 100 mg/kg feed, corresponding with 10 mg/kg bw/day.

In a 30 day dermal repeated dose toxicity (Hoechst, 1967) chloroacetamide was tested without coverage in female rabbits at 25, 50, 100, 200 and 400 mg/kg bw /day (0.063, 0.13, 1.25, 0.50, 1.00 mL/kg bw/day). After the end of testing all surviving animals were observed for 3 days. In the 25 and 50 mg dose groups there were no findings. In the 100 mg dose group a slight body weight loss was observed during treatment and histological changes in liver, heart muscle and spleen. In the 200 mg dose group similar observations were done with a more significant weight loss. In the 400 mg dose group 3 animals died (1 on day 1, 2 and 3 respectively). Similar changes as in the 100 and 200 mg dose groups in liver, heart muscle and spleen were observed and a significant weight loss. In all dose groups there were local changes of the treated skin area (encrustation to induration). The dermal NOAEL was 50 mg/kg bw/day.

In a 13 weeks dermal toxicity repeated dose study, Konservierungsmittel CA 24 was applied to the shaved backs of male adult Wistar-rats, at doses of 12.5 and 50.0 mg/kg in Lanette (1 or 2%) or Aqua dest (2%). Neither test dependent or substance specific changes were observed in the growth parameters and histomorphological examinations. The dermal “no-effect” level of CA 24 in male adult rats is 50 mg/kg bw. Taking into account the 70% Chloroacetamide content and assuming that sodium benzoate was inactive on the skin, 35 mg act./kg bw was considered as local NOAEL. Based on the lower NOAEL, this was considered as key study. Considering a mean body weight of 300 g (based on study data) and a surface area of 325 cm2 (Derelanko, 2008; The Toxicologist's Pocket handbook p29), 10.5 mg was applied on 32.5 cm2 (10% body surface), corresponding to 0.32 mg/cm2. Compared to the rabbit NOAEL of 50 mg/kg bw and a mean body weight of 2.5 kg (based on study data) and a surface area of 1270 cm2 (Derelanko, 2008; The Toxicologist's Pocket handbook p29), 125 mg was applied on 127 cm2 (10% body surface), corresponding to 0.98 mg/cm2. Therefore the rat value was considered most conservative.

As the key 3-month dermal study (IBR, 1971; NOAEL = 50 mg/kg bw) did not have biochemistry and full histopathology, the NOAEL from the 90-day oral study was used as most conservative. In a key 90 day oral repeated dose study (Hoechst, 1985) 80 Wistar rats (40 males and 40 females) were administered at doses of 0, 20, 100 and 500 mg Chloroacetamide/kg feed /day (equivalent to 0, 2, 10 and 50 mg/kg bw/day). In the high dose group, reduced body weight gain/food consumption and increased leucocytes were observed, as well as decreased liver weights in females, and smaller testes, reduced testicular weights, proliferation of Leydig cells and depression - standstill of spermiogenesis in males. After a 29 -day recovery period, partial to complete regeneration was observed in the testis, therefore this was considered to be reversible. The NOAEL was 100 mg/kg feed, corresponding with 10 mg/kg bw/day.