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Administrative data

Description of key information

Oral repeated dose toxicity was examined in a key 90-day study and 3 supporting 28- and 90-day studies in rats. Testes, liver, kidney and thyroids were identified as target organs.  The overall oral NOAEL was determined to be 10 mg/kg bw/day.
In a key and a supporting dermal repeated dose toxicity study the dermal NOAEL was determined to be 50 mg/kg bw/day.
2 Supporting repeated dose studies with subcutaneous or intravenous administration of Chloroacetamide both resulted in a NOAEL of 10 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted under GLP and it was done according to valid methods, therefore it is considered relevant, reliable and adequate for classification.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
EU Method B.27 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)
Deviations:
yes
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Principles of method if other than guideline:
No. of animals per group was limited to 10, of which the first 5 were the main group and the next 5 were used for 29-day recovery. This is not considered to impact the study as there is extensive dose response information from other 28- and 90-day toxicity studies.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Wistar: Hoe: WISKf(SPF71)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hoechst AG, Hattersheim-Kastengrund (Germany), SPF-Zucht,
- Age at study initiation: Males ca. 4 weeks; females ca. 5 weeks
- Weight at study initiation: Average males 79.8 g; average females 85.4 g
- Housing: Draft mesh cages (Type 3), in groups until 2 animals
- Diet: Rattendiät Altromin 1321 by Altromin GmbH Lage/Lippe (Germany) ad libitum
- Water: Tap water in plastic bottles, ad libitum
- Acclimation period: At least 5 days before study

ENVIRONMENTAL CONDITIONS
Fully airconditioned rooms

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: 1kg premix of the 10 fold end concentration was mixed together with 9 kg Altromin 1321 in a ploughshare mixer for 20 minutes. Every mixture was examined analytically for concentration and homogeneity of the test substance.

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Rattendiät Altromin 1321
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Extraction of the active ingredient from the spiked diet using methanol (Chromasolv R). Concentration and dilution in methanol
(Chromasolv R). Determination of the active ingredient using gaschromatography with a nitrogen selective detector (PND).
(cf report Dr. Thier dd 1984-07-12 / encluded in the study report)
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 2, 10, 50 mg/kg bw/day
Basis:
nominal in diet
No. of animals per sex per dose:
10 (of which the first 5 animals were used as the main group, and the next 5 animals for 29-day recovery)
Control animals:
yes
Details on study design:
- Dose selection rationale: In an earlier 90 days oral repeated dose study doses of 12.5 and 50 mg/kg bw/day were administered. These doses were too high to determine a no effect level. Purpose of this experiment was to determine a no effect level.
- Rationale for selecting satellite groups: first 5 animals of each group were killed at the end of testing; the other 5 were killed after 29 days recovery period.
- Post-exposure recovery period in satellite groups:29 days
Observations and examinations performed and frequency:
-Monday - Friday 2x daily, on weekends 1x daily: behaviour /health state
-1x weekly: neurological disorders, opacities of eyes, injuries of the mouth's mucous membrane, disturbed toothgrowth
-2x weekly, during acclimation, study and recovery: body weight
-2x weekly during study: feed used; 1x weekly water used
-end of study or end of recovery period: haematological parameters in the blood: Hemoglobin; Erythrocyte count, Leucocyte count, Hematocrit, Reticulocyte count *, Heinz bodies *, Differential Blood Count, Platelet Count, Clotting time (* only in the control group and high dose group)
-after sacrifice: clinical-chemical parameters in the serum: Sodium, Potassium, Inorganic Phosphorus, Uric acid, Bilirubin total, Creatinine, Serum glucose, Urea-N (BUN), Calcium, Chloride, SGOT, SGPT, Alk. Phospatase
-night between 88./89. study day, 16 h urine: urinanalysis (animals unfeed, unwatered): Appearance, Color, Protein, Glucose, Hemoglobin, Bilirubin, pH value, Ascorbic acid, Ketone bodies, Density * (only from high dose and control group), Sediment









Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- Sacrifice by i.p. injection of 50 mg Nembutal / kg bw / de-bleeding by opening the vena cava cranialis
- gross assessment according to Hoechst Sektionsordnung I, Prof. K/G dd 1982-02-04
-relative organ weights (% of bw)
HISTOPATHOLOGY: Yes
- histological assessment of fixated organ or preparations according to Hoechst Sektionsordnung I, Prof. K/G dd 1982-02-04: heart, lungs, liver, kidneys, spleen, stomach, jejunum, colon, bladder, testes, epidiymis, prostate, seminal vesicle, ovaries, uterus,thyroid, pancreas, adrenals, thymus, pituitary gland, brain, eyes with N. opticus, bone marrow (femur marrow)
Other examinations:
Feed analysis (see Table 1)
Statistics:
Statistical evaluation of following measured values, using probability level 0.05:
- body weight at observation times
- body weight gain during intervals
- haematological parameters (except differential blood count)
- clinical chemical parameters
- urinanalysis (pH, density)
- absolute/ relative organ weights
Hoechst evaluation software used according to SOP Dr. Passing, Department of Practical Mathematics.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: no effects, no mortalities during dosing & recovery period.
BODY WEIGHT AND WEIGHT GAIN: decreased in males & femaels in highest dose from week 2/3 onwards, respectively; reversible in recovery period.
FOOD CONSUMPTION AND COMPOUND INTAKE: decreased in males & females during first 30 days. No effects in recovery period.
FOOD EFFICIENCY: no data
WATER CONSUMPTION: no effects during dosing & recovery period.
OPHTHALMOSCOPIC EXAMINATION: no effects during dosing & recovery period.
HAEMATOLOGY: increased white blood cells at highest dose; reversible in recovery period.
CLINICAL CHEMISTRY: no effects during dosing & recovery period.
URINALYSIS: no effects during dosing & recovery period.
NEUROBEHAVIOUR: no effects during dosing & recovery period.
ORGAN WEIGHTS: male rats, highest dose: reduced testicular weights; still observed in the recovery group - decreased liver weight in females, highest dose; reversible in recovery period however decreased liver weight in males after recovery period.
GROSS PATHOLOGY: male rats, highest dose: smaller testes, reversible in the recovery group
HISTOPATHOLOGY: male rats, highest dose: depression - standstill of spermiogenesis and proliferation of Leydig cells and other interstitial cells in testes; absence of mature & immature sperms instead only loose connective tissue visible in epidydimides; in the recovery group starting to complete regeneration was observed.



Dose descriptor:
NOAEL
Effect level:
100 mg/kg diet
Based on:
test mat.
Sex:
male/female
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Critical effects observed:
not specified

Table 1 Feed analysis

Mixture 1 (11.01.1984) Means
Dose mg/kg added    days after mg/kg found     mg/kg in
mg/kg test subst. act.ingr. preparation Act. Ingr. Test subst.   feed (real)
20 20,1 20 1 19 19    
20 20,1 20 1 14 14   16,5
100 100 99,8 1 92 92    
100 100 99,8 1 81 81   86,5
500 500 499 1 453 454    
500 500 499 1 479 480   467
Mixture 2 (22.02.1984)
Dose mg/kg added    days after mg/kg found     mg/kg in
mg/kg test subst. act.ingr. preparation Act. Ingr. Test subst.   feed (real)
20 20 19,9 1 16 16    
20 20 19,9 1 13 13   14,5
100 100 99,7 1 77 77    
100 100 99,7 1 78 78   77,5
500 500 499 1 396 397    
500 500 499 1 381 382   389,5
Mixture 3 (24.04.1984)
Dose mg/kg added    days after mg/kg found     mg/kg in
mg/kg test subst. act.ingr. preparation Act. Ingr. Test subst.   feed (real)
20 20 19,9 1 14 14    
20 20 19,9 1 14 14   14
100 100 99,7 1 63 63    
100 100 99,7 1 68 68   65,5
500 500 499 1 362 363    
500 500 499 1 361 362   362,5
Overall means
Nomimal doses feed Measured doses feed
mg/kg mg/kg
20 15,0
100 76,5
500 406,3
Conclusions:
Chloroacetamide in this 90 day oral repeated dose study in rats caused a decreased body weight gain and increased leucocyte count in the high dose male and female rats. The high dose males had smaller testes, depression- standstill of the spermiogenesis and proliferation of Leydig cells. After a 29 day recovery period, there were signs of beginning or ended regeneration of the testicular tubuli.
The NOAEL for Chloroacetamide in this study was determined to be 10 mg/kg bw/day.
Executive summary:

In a 90 day oral repeated dose study in Wistar rats were given doses of 0, 20, 100 and 500 mg Chloroacetamide test substance/kg feed /day. Each group consisted of 10 male and 10 female animals, of which the first 5 animals of each group, were killed at the end of the 90 day, whereas the other 5 were killed after a 29 day recovery period. In the high dose (500 mg/kg feed) male and female animals showed reduced body weight gain and food consumption and increased leucocytes in both sexes, decreased liver weights in females, and smaller testes, reduced testicular weights, proliferation of Leydig/other interstitial cells and depression - standstill of spermiogenesis in males.Re-onset in the recovery group with partial to complete regeneration of testes was observed in males, therefore this was to be designated as reversible. Further liver weights were reversed in females and slightly decreased in males in the hightest dose recovery groups. The NOAEL was determined to be 100 mg/kg feed, which was reported to correspond with 10 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
High (Klimisch 1)

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: The study was conducted before GLP application and only limited details were available, therefore it is considered less reliable and adequate for classification.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
1 sex only (the impact is considered limited)
Principles of method if other than guideline:
Hoechst AG Guideline
GLP compliance:
no
Limit test:
no
Species:
rabbit
Strain:
other: Yellow-Silver breed
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: average 2.46 kg (1.89-3.14 kg)
- Housing: Individual cages
- Diet: Standard-Futter Altromin K (Altromin GmbH, Lage/Lippe (Germany))
- Water: Tap water
Type of coverage:
open
Vehicle:
water
Details on exposure:
Hair depilated in the neck area, on which chloroacetamide was applied as a 40% aqueous solution.
Using a frill of synthetic material, animals were prevented from licking off / orally taking-up the substance
Duration of treatment / exposure:
30 days
Frequency of treatment:
1x daily
Remarks:
Doses / Concentrations:
0, 25, 50, 100, 200, 400 mg/kg bw/day
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
0, 0.063, 0.13, 0.25 0.50, 1 mL/kg
Basis:
other: volume/kg body weight
No. of animals per sex per dose:
5 females
Control animals:
yes, concurrent no treatment
Details on study design:
During the study + the 3 day recovery period, animals received a standard diet Altromin K by Altromin GmbH Lage/Lippe
(Germany) as well as tap water.
Observations and examinations performed and frequency:
Before the study and after its end, blood count and urinanalysis of all animals were done.
Sacrifice and pathology:
After the recovery period, all surviving animals were sacrificed by rabbit-punch and de-bleeding. The bodies were dissected and
the organs heart, lung, both kidneys, liver and spleen were histologically examined.
The same procedure was done for animals which had died during the study - except animal 479 of the highest dosage group
which died after the first application.
Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
liver, heart muscle,Hoechst, 1967) spleen
Details on results:
From 100 mg/kg bw/day on, a dose-related weight loss was observed.
At 100 and 200 mg/kg bw/day, dose-related histological changes were observed in the liver and heart (lipid metabolism changes) and spleen (haemosiderin deposition).
Applications of 400 mg/kg bw/day lead to lethality 3/5: 1 animal died after the 1st, 1 after the 2nd and another after the 3rd dosage.
At all dosages, encrustation to induration of the application site was observed.

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
other: Sytemic NOAEL
Critical effects observed:
not specified
Conclusions:
In the 25 and 50 mg dose groups there were no systemic effects, whereas at 100, 200 and 400 mg dose groups histological changes in liver, heart muscle and spleen and a dose dependent weight loss were observed . 3 Animals died in the highest dose group. In all dose groups there were local changes of the treated skin area (encrusted to hardened).
Executive summary:

In a 30 day dermal repeated dose toxicity study in female rabbits, chloroacetamide was tested without coverage (open) in one control and 5 dose groups of each 5 female rabbits at 25, 50, 100, 200 and 400 mg/kg bw /day ( 0.063, 0.13, 1.25, 0.50, 1.00mL/kg bw/day). 3 Days 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. One animal died, but this was not related to the administered substance. 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).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
Limited (Klimisch 3)

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was done with a formulation having a different composition (70% Chloroacetamide; 30% sodium benzoate), however it was considered reliable, adequate and relevant for classification and local DNEL calculation. As there is no clinical biochemistry and only limited histopathology, the study cannot be used for systemic DNELs.
Principles of method if other than guideline:
IBR guideline
GLP compliance:
no
Limit test:
yes
Species:
rat
Strain:
other: Wistar SPF
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Paderborn
- Age at study initiation: Adult
- Weight at study initiation: Average ca. 210 g
- Housing: Individual cages
- Diet: Rattenstandardiät (ssniff/Intermast), ad libitum
- Water: Ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1°C
- Humidity (%):45-55%
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
open
Vehicle:
water
Details on exposure:
The test substance was dissolved in water, pure or supplied with 1-2 % Lanette R.
Back of animals had been partly shorn.
Using a glass rod, the test solution was applied daily onto the shorn areas.
Duration of treatment / exposure:
3 months / 13 weeks
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 12.5, 50.0 mg/kg
Basis:
nominal per unit body weight
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
Control: Lanette; Group I, 12.5 mg/kg in Lanette 1 %; Group II, 50.0 mg/kg in Lanette 2 %; Group III, 50.0 mg/kg in aqua dest 2 %;
Observations and examinations performed and frequency:
clinical symptoms : daily
body weight, weight gains, feed use, feed efficiency, water used : weekly
Sacrifice and pathology:
section: weights of heart, liver, kidneys, adrenal glands, testicles
histology: testicles
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: clinical signs; mortality; body weight; food consumption; gross pathology; organ weights; histopathology
Critical effects observed:
not specified
Conclusions:
The dermal “no-effect” level of CA 24 in male adult rats is 50 mg/kg bw.
Executive summary:

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 or Aqua dest. 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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
0.32 mg/cm²
Study duration:
subacute
Species:
rat
Quality of whole database:
High (Klimische 2)
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.

Additional information

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 act.ingr./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's cells and depression - standstill of spermiogenesis in males. A reduction in testicular and epididymal size was seen. Histopathological examination revealed depression and/or cessation of spermiogenesis as well as moderate proliferation of Leydig’s cells. The epididymis contained neither mature nor immature sperm cells, only cross-linked protein. No other histopathological changes were observed in the males. The females of all dose groups were without histopathological findings. Follicle maturation was found to be normal. In the groups receiving 100 and 20 mg/kg feed ‘approximately 10 and 2 mg/kg body weight/day), no substance-related organ changes were seen. After a 29 -day recovery period, partial to complete regeneration was observed in the testis. The NOAEL was 100 mg/kg feed, corresponding with 10 mg/kg bw/day.

Various supporting oral studies in rats provided additional dose response and target organ information:
- a 28 days study by oral gavage (Hoechst, 1958) showed increase in urinary protein; dose dependent macroscopic histological changes in liver (degenerative changes) and kidneys (changes attributed to trichloro acetic acid), with NOAEL = 10 mg/kg bw/day;
- a 90 day study with Chloroacetamide in the feed in Sprague-Dawley rats dosed at 12.5 and 50 mg/kg bw (Leuschner, 1970) showed inhibition of body weight gain, shaggy fur, enlarged thyroid glands (females), smaller testes in males, with dose related histological disturbance of spermatogenesis and seminiferous tubules almost cell-free, with NOAEL < 12.5 mg/kg bw/day.
- a 90 day study with Chloroacetamide in the feed in Sprague-Dawley rats (Kemper, 1989) also showed decreased body weights and soft/small testes with impaired spermiogenesis in males dosed at 12.5 and 50 mg/kg feed; decreased food consumption and histological liver changes (starting fatty liver degeneration and atrophy) in both sexes at 50 mg/kg; increased thyroid weights only in females dosed at 50 mg/kg; NOAEL<12.5 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/kg dose group a slight body weight loss was observed during treatment and histological changes in liver, heart muscle (lipid metabolism changes) and spleen (haemosiderin deposition). In the 200 mg /kg bw 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/kg bw 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 systemic 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.ingr./kg bw was considered as local NOAEL. Based on the longer duration and the lower NOAEL, this was considered as key study for local DNEL derivation.

Inhalation is unlikely as vapour pressure is too low and particle size is too high for potential inhalation toxicity. Therefore, inhalation testing is waived.

Two supporting 30 days repeated dose studies (Hoechst, 1967a & b) were available, where chloroacetamide was administered up to doses of 100 mg/kg bw by subcutaneous and intravenous route, respectively. The NOAEL in both studies was 10 mg/kg bw/day, whereas clinical (nervous system) observations and mortality appeared from 25 mg/kg onwards. These studies however were not relevant for classification, so they were disregarded.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Key study; the study was conducted under GLP and it was done according to valid methods, therefore it is considered relevant, reliable and adequate for classification.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Supporting study; the study was conducted before GLP application and only limited details were available, therefore it is considered less reliable and adequate for classification.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Key study with longest (90 day) duration; the study was done with a formulation having a different composition (70% Chloroacetamide; 30% sodium benzoate), however it was considered reliable, adequate and relevant for classification and local DNEL calculation.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; glandular: thyroids; urogenital: kidneys; urogenital: testes

Repeated dose toxicity: dermal - systemic effects (target organ) cardiovascular / hematological: heart; cardiovascular / hematological: spleen; digestive: liver

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 2 classification is proposed with Signal word 'Warning' and hazard statement H373 'MAY CAUSE DAMAGE TO ORGANS (TESTES, LIVER, KIDNEY) THROUGH PROLONGED OR REPEATED EXPOSURE (ORAL, 28 -90 DAYS)'.

Based on these results and according to the EC Directive (No.93/21/EEC) and CLP (No. 1272/2008 of 16 December 2008),

Chloroacetamide is proposed to be classified for repeated dose STOT Category 2 classification.