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Description of key information

Oral acute toxicity of Chloroacetamide was tested according to standard acute method in rats, mice, rabbits and dogs, resulting in an LD50 of 138 mg/kg bw in rats as relevant threshold for classification.  Dermal acute toxicity was tested according to standard acute method in rats, resulting in an LD50 >2000 mg/kg bw.  Inhalation acute toxicity was scientifically unjustified due to low vapour pressure.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted before GLP application, however it was done according to valid methods, therefore it is considered relevant, reliable and adequate for classification.
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Principles of method if other than guideline:
Method: other: Hoechst AG guideline
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Own breeding (Hoechst)
- Weight at study initiation: 80-110g (average 95g)
- Fasting period before study: 16 hours
- Housing: In polymer cages on wood shavings
- Diet (e.g. ad libitum): Altromin 1324 by Altromin GmbH, Lage/Lippe, Germany,
ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum

IN-LIFE DATES: From: 1976.08.30 To:1976.09.20
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
1% aqueous solution of chloroacetamide used.
Single application by pharyngeal tube.
Doses:
80, 125, 160, 200, 320 mg/kg bw
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: weekly
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:
LD50 was determined by probit analysis (according to LINDER and WEBER), confidence limits were calculated according to CAVALLl-SFORZA.
Sex:
female
Dose descriptor:
LD50
Effect level:
138 mg/kg bw
Based on:
test mat.
95% CL:
127 - 149
Mortality:
80 mg/kg bw: 0 of 10 rats; 125 mg/kg bw: 2 of 10 rats;
160 mg/kg bw: 9 of 10 rats; 200 mg/kg bw: 10 of 10 rats;
320 mg/kg bw: 10 of 10 rats.
Clinical signs:
Deadly poisoned animals showed impaired balance, gasping breathing and bended posture.
Body weight:
No effects reported.
Gross pathology:
No macroscopically effects were observed.

Table 1. Results

Dosis

mg/kg

Concentration

 in %

Number of dead animals/ number of tested animals

80

1

0/10

125

1

2/10

160

1

9/10

200

1

10/10

320

1

10/10

Interpretation of results:
moderately toxic
Remarks:
Migrated information Criteria used for interpretation of results: other: W.S.SPECTOR : Handbook of Toxicology
Conclusions:
The acute oral toxicity test in female SPF-Wistar rats resulted in an LD50 of 138 mg/kg bw. Chloracetamid at a single oral application is classified as moderately toxic after W.S. SPECTOR in the “Handbook of Toxicology”.
Executive summary:

Chloracetamid was tested after single oral gavage in female SPF-Wistar rats. Preliminary tests demonstrated higher sensitivity in female animals. The rats were fasted for 16 hours before and 2 hours after application. The animals were observed 14 days after application and weighed weekly. Deadly poisoned animals were dissected and assessed macroscopically; these animals showed impaired balance, gasping breathing and bended posture. After the study period, surviving animals were sacrificed and dissected macroscopically. No macroscopically effects were observed. Chloracetamid had an LD50 of 138 mg/kg bw and is classified as moderately toxic according to W.S. SPECTOR in the “Handbook of Toxicology”.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
138 mg/kg bw
Quality of whole database:
High (Klimisch 2)

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to GLP and current guidelines, and is considered relevant, reliable and adequate for classification.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: HSD: Sprague Dawley SD (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: HARLAN WINKELMANN, 33178 Borchen (Germany)
- Age at study initiation: 6-10 weeks
- Weight at study initiation: males 254g (241-267g); females 220g (213-233g)
- Housing: In macrolon cages (type 3) on soft wood granulate, one animals per cage
- Diet: ssniff" R/M-H (V 1534), ad libitum
- Water: tap water in plastic bottles, ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 50 ± 20 %
- Air changes (per hr): fully air-conditioned rooms
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
other: deionized water
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal skin over an area of approximately 30 cm2
- % coverage: 6 x8 cm
- Type of wrap if used: The appropriate amount of the test substance was moistened on a two-ply gauze and an aluminum foil (6 x 8 cm) and distributed as uniformly as possible. Together with the foil the test substance was administered to the shaved and intact dorsal skin. The foil was held in place with an elastic piaster bandage fixed around the animal's body.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration (if solution): Not provided



Duration of exposure:
24 h
Doses:
2000 mg/kg
No. of animals per sex per dose:
5
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations twice every day (in the morning and in the afternoon), on weekends and public holidays only once; weighing weekly
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the whole study.
Clinical signs:
No symptoms were observed after administration of 2000 mg/kg body weight.
The skin of the animals showed no signs of irritation.
Body weight:
Three female animals showed a disturbance of body weight gain during the first week of the study, which
returned to normal until the end of the study. In all other animals development of body weight was not impaired.
Gross pathology:
The animals killed at the end of the observation period showed no macroscopically visible changes.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the results obtained in this study the acute dermal LD50 of Chloroacetamide for male and female rats is greater than 2000 mg/kg body weight.
Executive summary:

Acute dermal toxicity of Chloroacetamide was tested in 5 male and 5 female Sprague-Dawley rats at a dose of 2000 mg/kg bw under occlusion. At the end of the dermal exposure period of 24 hours the bandage was removed and the treated skin area washed with warm water in order to remove any unabsorbed remnants of the test substance. The observation period after the dermal administration lasted for 14 days.

No deaths and no symptoms occurred. The skin of the animals showed no signs of irritation. Three female animals showed a disturbance of body weight gain during the first week of the study, which returned to normal until the end of the study. In all other animals development of body weight was not impaired. The animals killed at the end of the observation period showed no macroscopically visible changes.
Based on the results obtained in this study the acute dermal LD50 of Chloroacetamide for male and female rats is greater than 2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
High (Klimisch 1)

Additional information

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.

Supporting data were available for other species (Hoechst, 1958; Expert Panel on Cosmetic Ingredients, 1991):

- The acute oral LD50 of Chloroacetamide in mice according to standard method (non-GLP) was 150 mg/kg bw

- The acute oral LD50 of Chloroacetamide in rabbits according to standard method (non-GLP) was 122 mg/kg bw

- The acute oral LD50 of Chloroacetamide in dogs according to standard method (non-GLP) was 31 mg/kg bw.

In another supporting study (IBR ,1988), acute oral toxicity testing of a formulation containing 70% Chloroacetamide & 30% sodium benzoate, provided LD50 values of 275 and 306 mg/kg bw in male and female rats. Reduced activity (apathy),tonic/clonic convulsions, tremor and twitches, disturbance of coordination, cyanosis, piloerection and reduced respiration rate were observed in the dosed animals. Post-mortem changes included residues of the sample and redness of the mucous membrane of the digestive tract. Nothing abnormal was found in the animals necropsied on day 14.

Acute inhalation testing was waived as the vapor pressure of Chloroacetamide was very low (0.0026-0.0078 hPa measured at 20 -30 °C; 0.0106 mm Hg calculated at 25°C). Based on Column II of REACH annexes, inhalation toxicity testing is scientifically unjustified.

In a key acute dermal toxicity limit study conducted under GLP (Aventis ProTox , 2001), Chloroacetamide tested in male and female Sprague-Dawley rats resulted in an LD50 greater than 2000 mg/kg bw under occlusion according to OECD 404 method. No deaths, clinical observations nor gross patholological changes occurred. The skin of the animals showed no signs of irritation. Three female animals showed a disturbance of body weight gain during the first week of the study, which returned to normal until the end of the study. In all other animals development of body weight was not impaired. The animals killed at the end of the observation period showed no macroscopically visible changes. Based on the results obtained in this study the acute dermal LD50 of Chloracetamide for male and female rats is greater than 2000 mg/kg body weight.

Finally, supporting data of lower reliability were also available for other routes; some examples are provided below, however these were not further taken into account for classification:

- The acute intraperitoneal LD50 in mice was reported to be 130 mg/kg bw (Kemper, 1989; IBR, 1979) or 100 -150 mg/kg bw (Expert Panel on Cosmetic Ingredients, 1991)

- The acute intraperitoneal LD50 in chinese hamsters was 150 mg/kg bw (Kemper, 1989)

- Intraperitoneal administration of 75 mg/kg bw in rats indicates that hepatic GSH depletion leads to lipid peroxidation, which can be significantly increased without causing permanent damage to hepatocytes (Anundi et al., 1980)

- The acute intraperitoneal LD50 in rats was 50 mg/kg bw (Nielsen, 1983).


Justification for selection of acute toxicity – oral endpoint
Key study; the study was conducted before GLP application, however it was done according to valid methods, therefore it is considered relevant, reliable and adequate for classification.

Justification for selection of acute toxicity – dermal endpoint
Key study; the study was conducted according to GLP and current guidelines, and is considered relevant, reliable and adequate for classification.

Justification for classification or non-classification

Chloroacetamide was classified according the EU labelling regulations Commision Directive 93/21/EEC as HARMFUL with symbol 'Xn' and risk phrase R 25 'HARMFUL IF SWALLOWED'. According to CLP regulation (No. 1272/2008 of 16 December 2008), Category 3 classification is proposed with Signal word 'Danger' and hazard statement H301 'TOXIC IF SWALLOWED'.

Based on these results and according to the EC Directive (No.93/21/EEC) and CLP (No. 1272/2008 of 16 December 2008), Chloroacetamide does not have to be classified and has no obligatory labelling requirement for dermal toxicity.