Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
From October 29, 2001 to June 18, 2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
RA study
Justification for type of information:
Refer to the section 13 for details on the read across justification. The repeated dose toxicity (oral) study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.
Reference:
Composition 1
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
- Physical state: Pale straw coloured liquid
- Analytical purity: 35.5% coco alkyl trimethyl ammonium chloride, 64.5% water
- Lot/batch No.: RHO20010082
- Storage condition of test material: Room temperature, in the dark
Species:
rat
Strain:
other: Sprague-Dawley, Crl:CD® (SD) IGS BR
Sex:
male/female
Details on test animals and environmental conditions:
- Source: Charles River (UK) limited, Margate, Kent
- Age at study initiation: 6 wk
- Weight at study initiation: Males: 141-183g, females: 132-161g
- Acclimation period: 14d

ENVIRONMENTAL CONDITIONS
- Temperature: 21±2°C
- Humidity: 55±15%
- Photoperiod (hrs dark / hrs light): 12h/12h
Route of administration:
oral: feed
Vehicle:
other: mixed with diet
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Mean dietary admixture concentrations were within acceptable limits for the purpose of the study (Gas chromatography).
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily in feed
Remarks:
Doses / Concentrations: 0, 100, 500 and 2000 ppm (equivalent to 22, 113 and 273 mg/kg bw/day after correction of 35.5% purity); the highest dose of 2000 ppm was reduced to 1000 ppm from Day 29 onwards due to deterioration in health of treated animals at 2000 ppm.
Basis: nominal in diet
No. of animals per sex per dose:
10 males and 10 females per dose
Control animals:
yes, plain diet
Details on study design:
- Post-exposure recovery period in satellite groups: None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0 (the day before start of treatment) and weekly thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Weekly throughout the study

FOOD EFFICIENCY: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily for each cage group

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Before start of treatment and before termination of treatment (during week 12)
- Dose groups that were examined: All

HAEMATOLOGY: Yes
- Time schedule for collection of blood: End of treatment (Day 90)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: End of treatment (Day 90)

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Day 0 (the day before start of treatment) and weekly thereafter
- Dose groups that were examined: All
- Battery of functions tested: Sensory activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals
HISTOPATHOLOGY: Yes, Macroscopic lesions, Adrenals, Aorta, Bone and bone marrow (femur including stifle joint), Bone and bone marrow (sternum), Brain (including cerebrum, cerebellum and pons), Cecum, Colon, Duodenum, Epididymides, Eyes, Gross lesions, Heart, ileum, Jejunum, Kidneys, Liver, Lungs (with bronchi), Lymph nodes (cervical and mesenteric), Mammary gland, Muscle (skeletal), Oesophagus, Ovaries, Pancreas, Pituitary gland, Prostate, Rectum, Salivary glands (submaxillary), Sciatic nerve, Seminal vesicles, Skin (hind limb), Spinal cord (cervical), Spleen, Stomach, Testes, Thymus, Thyroid/parathyroid, Tongue, Trachea, Urinary bladder, Uterus.
Statistics:
Data were processed to give group mean values and standard deviation where appropriate. Haematological, blood chemical, organ weight, weekly body weight gain and quantitative functional performance and sensory reactivity data were assessed for control and test substance treatment groups for dose response relationship by linear regression analysis, followed by one way analysis of variance (ANOVA) incorporating Levene's test for homogeneity of variance. Where variances were shown to be homogenous, pairwise comparisons were conducted using Dunnett's test. Where Levene's test showed unequal variances, the data were analysed using non-parametric methods: Kruskal-Wallis ANOVA and Mann-Whitney 'U' test.
Clinical signs:
no effects observed
Description (incidence and severity):
High dose animals developed clinical signs of toxicity from Day 7 onwards. These included hunched posture, pilo-erection, tiptoe gait, diarrhoea and red/brown staining of external body surface. Due to these effects, the dose level was reduced to 1000 ppm from Day 29 onwards. Clinical signs persisted following the reduction in dose level and included two incidents of pallor of extremities together with generalised fur loss. No clinically observable signs of toxicity were detected at the mid and the high doses.
Mortality:
no mortality observed
Description (incidence):
No mortality occurred during the study period.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduced body weight gain was detected for high dose animals of either sex during the first five weeks of the study compared with controls. Mid dose males were similarly affected but this was confined to week 1 and 2 only. Body weight gain recovered following reduction in the dose level and was comparable with controls thereafter but terminal bodyweights for high dose animals and mid dose males remained lower than controls. No adverse effect on bodyweight gain was detected for 500 ppm females or for animals of either sex treated with the low dose.

Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduced food intake was observed in the high and mid dose animals throughout the study period compared with controls.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Food efficiency was reduced over the first three weeks of the study but this was confined to the high dose group only. No adverse effect on dietary intake or food efficiency was detected at the low dose.
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No appreciable intergroup differences were detected. High dose animals showed a reduced water intake on Day 6 of the study which recovered thereafter.
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
- Detailed open-field observations conducted during the study confirmed the clinical signs of hunched posture, pilo-erection and tiptoe gait detected in high dose animals. No such effects were detected at the mid or low dose levels.
- Functional performance test: No treatment-related changes were detected.
- Sensory Reactivity Assessments: High dose females showed an increase in startle reflex parameters compared with controls. No such effects were detected for high dose males or for animals of either sex treated with the lower doses.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
No toxicologically important organ weight changes were detected. The reductions in absolute weight (including heart, kidneys, liver and thymus weight at the high dose and heart weight at the mid dose) and increases in relative weight (including high dose brain epididymides, kidneys, spleen, testes and ovaries weight), were all considered to be a result of reduced bodyweight development rather than test substance toxicity.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related macroscopic abnormalities.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related changes were observed in the spleen and kidneys. Lower severities of pigment accumulation were observed in the spleen of high dose male rats but not for the females (p <0.05). A higher incidence of pigment accumulation was observed in the kidneys of the high and mid dose male rats. In both tissues the pigment reacted positively to Perl's staining technique and was considered to be haemosiderin.
Histopathological findings: neoplastic:
not specified
Key result
Dose descriptor:
NOEL
Effect level:
22 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: effects observed at 113 and 273 mg/kg bw/day
Key result
Dose descriptor:
NOAEL
Effect level:
113 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food efficiency
histopathology: non-neoplastic
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
273 mg/kg bw/day (actual dose received)
System:
other: microscopic changes in the spleen and kidneys of high dose animals
Organ:
kidney
spleen
Treatment related:
yes
Dose response relationship:
yes
Conclusions:
- Based on the results of the read across study, dietary administration of the test substance to rats for a period of 90 days at levels up to 273 mg ai.i/kg bw/day resulted in toxicologically significant effects at the high dose and marginal effects at the next lower dose of 113 mg ai.i/kg bw/day. No such effects were demonstrated at the lowest dose of 22 mg a.i./kg bw/day. Therefore, the NOEL was considered to be 22 mg a.i./kg bw/day.
(The changes observed at the mid dose were considered to be minor, isolated effects associated with the reduced palatability of the test substance and were considered not to represent an adverse health effect. Hence, for the purposes of hazard evaluation, the NOAEL should be regarded as 113 mg/kg bw/day.)
Executive summary:

A study was conducted to determine the oral repeated dose toxicity of the read across substance, quaternary ammonium compounds, C12-C18 (even numbered) alkyltrimethyl chloride (C12-18 TMAC), according to OECD Guideline 408 and EU Method B.26, in compliance with GLP. Sprague-Dawley rats were administered the test substance at concentrations of 0, 100, 500 or 2000 ppm, corresponding to 22, 113 and 273 mg a.i./kg bw/day) in the diet for 90 d. The highest dose of 2000 ppm was reduced to 1000 ppm from Day 29 onwards due to deterioration in health of the test animals at 2000 ppm. At the highest dose, the treatment-related findings were clinical signs of toxicity, reduced body weight gain and food efficiency, organ weight changes and microscopic changes in the spleen and kidneys. At the mid dose, reduced body weight gain (males) and reduced food consumption, reduced absolute heart weight and higher incidence of haemosiderin accumulation in the kidneys of males was observed. No treatment-related effects were observed at the lowest dose. Hence, the NOEL was considered to be 100 ppm (i.e. equivalent to 22 mg a.i./kg bw/day). The changes observed at 500 ppm were considered to be minor, isolated effects associated with the reduced palatability of the test substance and were considered not to represent an adverse health effect. The NOAEL was therefore 500 ppm (i.e. equivalent to 113 mg a.i./kg bw/day) (Jones, 2002).

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
RA study
Justification for type of information:
Refer to the section 13 for details on the read across justification. The repeated dose toxicity (oral) study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.
Reference:
Composition 1
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Version / remarks:
see 'Principles of method if other than guideline'
Deviations:
no
Principles of method if other than guideline:
Groups of 10 male and 10 female rats received test substance by oral gavage at the dose levels of 0, 30, 100 and 300 mg/kg bw/day for 28d. In addition, 5 male and 5 female animals were included in control and high dose group (recovery group). Animals were observed for clinical signs of toxicity, body weight changes, food and water consumption, haematological and biochemical parameters. Animals were necropsied and analysed for any visible abnormalities. Several tissues/organs were subjected to histopathological investigations in control and high dose group. Ophthalmological examination was also performed.
GLP compliance:
yes
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
- Analytical purity: 24-26%
- Lot/batch No.: 548050
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
Once daily
Remarks:
Doses / Concentrations:
0, 30, 100 and 300 mg/kg bw/day
Basis: other: The test substance used was a 24-26% aqueous solution but it is not clear if the doses mentioned are corrected for undiluted test substance.
No. of animals per sex per dose:
10 per sex per dose in main groups; 5 per sex in recovery groups (vehicle and highest dose group)
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for selecting satellite groups: To check the reversibility of the effects, if any
- Post-exposure recovery period in satellite groups: at least 27d
Observations and examinations performed and frequency:
Animals were observed for clinical signs of toxicity. Body weight, food and water consumption were recorded. Haematological and biochemical parameters were analysed. All animals were necropsied and checked for macroscopically visible abnormalities. Several tissues/organs were preserved and processed for histopathological investigations in control and high dose group. Additionally, eyes were examined with slit lamp microscope for any treatment-related abnormality.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
Animals in the recovery groups were observed for at least 27d after termination of the treatment.
Statistics:
Yes, no detail available in the summary.
Clinical signs:
no effects observed
Description (incidence and severity):
Symptoms of local irritation were observed in the high dose group during the last week of treatment.

Mortality:
no mortality observed
Description (incidence):
No deaths occurred throughout the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Total body weight gain was comparable to control in test groups.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The mean food consumption in all treated groups was comparable to the control.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Water consumption was significantly increased in all animals of the high dose group.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
The examination of the eyes by slit lamp microscope showed no treatment-related effects.

Haematological findings:
no effects observed
Description (incidence and severity):
The haematological examinations revealed no substance related variation from the control values.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
The highly significant increase in ALT-activity in the high dose group. The observed increase of the ALT-activity is considered to be an isolated finding as no other parameter is correlated with this deviation. Therefore, this finding is interpreted as incidental.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The absolute and relative organ weights such as spleen and adrenals showed some substance related changes in the males of high dose group.



Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
The macroscopical examination of the organs displayed substance related effects such as oedema of the mucosa of the forestomach, thickening of the mucosa and indication of ulceration in the animals of high dose group. Some additional observations like hydronephrosis, hydrometra and discolouration of the thymus showed no dose dependence and were therefore considered to be spontaneous. The observed irritative effects at the mucosa of the forestomach have been disappeared in the male and female animals of the recovery group 27d after termination of the treatment.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The forestomach of the male and female animals of the high dose group showed effects indicating local irritation like inflammatory oedema of the submucosa, sporadic ulceration and acanthosis of the mucosa up to papillomatous hyperplasia. These observations were considered to be due to the irritating properties of test substance and were considered not to be symptoms of a systemic toxicity. The animals of the recovery group of high dose showed a complete and regular regeneration of the forestomach mucosa.
Histopathological findings: neoplastic:
not examined
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
the test substance used was a 24-26% aqueous solution but it is not clear if the doses mentioned were corrected for undiluted test substance.
Sex:
male/female
Basis for effect level:
other: overall effects: no dose-dependent toxicologically significant effects up to the highest dose tested.
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
300 mg/kg bw/day (nominal)
Conclusions:
Based on the results of the read across study, the rat 28d NOAEL for systemic effects was determined to be 300 mg/kg bw/day.
Executive summary:

A study was conducted to determine the oral repeated dose toxicity of the read across substance, cetrimonium chloride (C16 TMAC), according to a method similar to OECD Guideline 407, in compliance with GLP. Groups of 10 male and female rats were administered 0, 30, 100 and 300 mg/kg bw/day test substance by oral gavage for 28 d. The test substance used was a 24-26% aqueous solution but it is not clear if the doses mentioned were corrected. There were no treatment-related changes at the 30 and 100 mg/kg bw/day. In the high-dose group there was an increase in water consumption, changes in the absolute and relative weights of the adrenals and spleens (inmales) without corresponding effects on haematology, clinical chemistry and histology. The forestomach of the high-dose group showed few microscopic changes, however animals in the high-dose recovery group showed a complete and regular regeneration of the forestomach mucosa. Hence, the forestomach effects were considered to be due to the irritating properties of the test substance rather than symptoms of systemic toxicity.Based on the results of the read across study, the rat 28 d NOAEL for systemic effects was determined to be 300 mg/kg bw/day (Potokar, 1991).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
113 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Both studies are conducted according to the OECD guideline as well as in compliance with GLP and have Klimisch score 1. The information requirements for this tonnage band is sufficiently met with the available data.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
RA study
Justification for type of information:
Refer to the section 13 for details on the read across justification. The repeated dose toxicity (inhalation) study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.
Reference:
Composition 1
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Type of coverage:
open
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure:
- % coverage: 25% of the body surface area.
- Time intervals for shavings or clipplings: all rabbits was abraded with a clipper head prior to the start of each application

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Following the exposure period, the treated skin surface was cleaned with water

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0 or 10 mg/kg bw/day
- Concentration (if solution): 0 or 0.5% aqueous solutions, respectively. The dosage volume was 2.0 mL/kg bw

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes, The animals were restrained with collars during the exposure period
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6.5 to 7 hours
Frequency of treatment:
5 days/week for 4 wks
Remarks:
Doses / Concentrations: 0 or 10 mg/kg/day
Basis: no data
No. of animals per sex per dose:
5 New Zealand albino rabbits/sex/group
Control animals:
yes, concurrent vehicle
Details on study design:
- Duration of observation period following administration: All rabbits were examined daily for clinical signs and mortality. Dermal irritation readings were recorded daily. The animals were weighed weekly during the exposure period. Blood was collected for haematology measurements before initiation of dosing and prior to termination. Liver and kidneys were weighed at necropsy. A complete list of tissues
was collected for histopathological evaluation
- Frequency of observations and weighing: weekly
- Necropsy of survivors performed: yes
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes / No / No data
- Time schedule: twice daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood was collected for haematology measurements before initiation of dosing and prior to termination

OTHER:
Mortality : twice daily
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes Liver and kidneys were weighed at necropsy. A complete list of tissues was collected for histopathological evaluation
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Treated areas of the skin that showed mild to marked acanthosis with active mitosis, hyperkeratosis, and partial to extensive necrosis of the epidermis and hair follicles, partly with encrustation and exudate
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
- Two control group animals died during the study.
- Slight to moderate erythema was observed in all treated rabbits between days 4 and 8, but disappeared in 4 rabbits by day 17. Very slight to slight oedema was observed between days 6 and 12 in 4 rabbits and subsided by day 17. Two rabbits had intermittent slight oedema during week 4, and one rabbit developed oedema on day 20. No evidence of desquamation or leather-like skin was present in these animals. In the other rabbits, slight atonia occurred up to week 4 in 3 animals. Slight skin fissuring was observed in most of the rabbits but typically disappeared by the end of the study. There were no treatment-related effects on body weight, haematology, organ weight, gross necropsy findings or histopathology, except for treated areas of the skin that showed mild to marked acanthosis with active mitosis, hyperkeratosis, and partial to extensive necrosis of the epidermis and hair follicles, partly with encrustation and exudate.
Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
dermal irritation
other: see 'Remark'
Key result
Critical effects observed:
no
Conclusions:
Based on the results of the read across study, the 28 d acute dermal NOAEL of the test substance for male and female rabbits was determined to be 10 mg/kg bw/day.
Executive summary:

A study was conducted to determine the repeated dose toxicity (inhalation) of the read across substance, cetrimonium chloride (C16 TMAC), according to a method similar to OECD Guideline 410. The experiment was performed in New Zealand albino rabbits (both sexes). The purity was not specified and the study included a lower than recommended number of animals (i.e. 10/group rather than 20/group as per guideline) and histopathology was performed only on limited organs. The test substance (0 and 10 mg test substance/kg bw/day) was applied to the shaved, intact skin of groups of 5 New Zealand albino rabbits/sex/group for 6.5 to 7 h, 5 d/week for 4 weeks. Dermal irritation readings were recorded daily. The animals were weighed weekly during the exposure period. Blood was collected for haematology measurements before initiation of dosing and prior to termination. Liver and kidneys weights were recorded at necropsy. There were no systemic treatment-related effects on body weights, haematology, organ weights, gross necropsy findings or histopathology. Treated areas of the skin showed mild to marked acanthosis with active mitosis, hyperkeratosis, and partial to extensive necrosis of the epidermis and hair follicles, partly with encrustation and exudate. Under the conditions of the study, the 28 d NOAEL for male and female rabbits was found to be 10 mg/kg bw/day (Spicer, 1979).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
One study available only. The information requirements for this tonnage band is sufficiently met with the available data.

Mode of Action Analysis / Human Relevance Framework

Additional information

Oral:

Study 1. A study was conducted to determine the oral repeated dose toxicity of the read across substance, quaternary ammonium compounds, C12-C18 (even numbered) alkyltrimethyl chloride (C12-18 TMAC), according to OECD Guideline 408 and EU Method B.26, in compliance with GLP. Sprague-Dawley rats were administered the test substance at concentrations of 0, 100, 500 or 2000 ppm, corresponding to 22, 113 and 273 mg a.i./kg bw/day) in the diet for 90 d. The highest dose of 2000 ppm was reduced to 1000 ppm from Day 29 onwards due to deterioration in health of the test animals at 2000 ppm. At the highest dose, the treatment-related findings were clinical signs of toxicity, reduced body weight gain and food efficiency, organ weight changes and microscopic changes in the spleen and kidneys. At the mid dose, reduced body weight gain (males) and reduced food consumption, reduced absolute heart weight and higher incidence of haemosiderin accumulation in the kidneys of males was observed. No treatment-related effects were observed at the lowest dose. Hence, the NOEL was considered to be 100 ppm (i.e. equivalent to 22 mg a.i./kg bw/day). The changes observed at 500 ppm were considered to be minor, isolated effects associated with the reduced palatability of the test substance and were considered not to represent an adverse health effect. The NOAEL was therefore 500 ppm (i.e. equivalent to 113 mg a.i./kg bw/day) (Jones, 2002).

Study 2. A study was conducted to determine the oral repeated dose toxicity of the read across substance, cetrimonium chloride (C16 TMAC), according to a method similar to OECD Guideline 407, in compliance with GLP. Groups of 10 male and female rats were administered 0, 30, 100 and 300 mg/kg bw/day test substance by oral gavage for 28 d. The test substance used was a 24-26% aqueous solution but it is not clear if the doses mentioned were corrected. There were no treatment-related changes at the 30 and 100 mg/kg bw/day. In the high-dose group there was an increase in water consumption, changes in the absolute and relative weights of the adrenals and spleens (inmales) without corresponding effects on haematology, clinical chemistry and histology. The forestomach of the high-dose group showed few microscopic changes, however animals in the high-dose recovery group showed a complete and regular regeneration of the forestomach mucosa. Hence, the forestomach effects were considered to be due to the irritating properties of the test substance rather than symptoms of systemic toxicity.Based on the results of the read across study, the rat 28 d NOAEL for systemic effects was determined to be 300 mg/kg bw/day (Potokar, 1991).

Dermal:

A study was conducted to determine the repeated dose toxicity (inhalation) of the read across substance, cetrimonium chloride (C16 TMAC), according to a method similar to OECD Guideline 410. The experiment was performed in New Zealand albino rabbits (both sexes). The purity was not specified and the study included a lower than recommended number of animals (i.e. 10/group rather than 20/group as per guideline) and histopathology was performed only on limited organs. The test substance (0 and 10 mg test substance/kg bw/day) was applied to the shaved, intact skin of groups of 5 New Zealand albino rabbits/sex/group for 6.5 to 7 h, 5 d/week for 4 weeks. Dermal irritation readings were recorded daily. The animals were weighed weekly during the exposure period. Blood was collected for haematology measurements before initiation of dosing and prior to termination. Liver and kidneys weights were recorded at necropsy. There were no systemic treatment-related effects on body weights, haematology, organ weights, gross necropsy findings or histopathology. Treated areas of the skin showed mild to marked acanthosis with active mitosis, hyperkeratosis, and partial to extensive necrosis of the epidermis and hair follicles, partly with encrustation and exudate. Under the conditions of the study, the 28 d NOAEL for male and female rabbits was found to be 10 mg/kg bw/day (Spicer, 1979).

Justification for classification or non-classification

Based on the observed effects and available NOAELs, it can be concluded that the test substance does not require classification according to Directive 67/548/EEC and Regulation (EC) 1272/2008.