Miristalkonium chloride

Endpoint summary

Description of key information

For the oral route, based on the effects observed in the 90-day read across study, the NOEL for the test substance, C14 ADBAC, can be considered to be at 500 ppm in the diet (i.e., equivalent to 31 mg/kg bw/day (or 25 mg a.i./kg bw/d) for males and 38 mg/kg bw/d (i.e. 30 mg a.i./kg bw/d) for females). With regard to the dermal route, a 20-day repeated dose dermal study available with C14 ADBAC in rabbits, revealed only local effects (severe erythema, oedema, thickening of the skin and eschar formation across the back) at the site of application without presence of any systemic effects. The NOAEL for systemic effects was therefore established at 3.2 mg/kg bw/day and the LOAEL for local effects at 0.8 mg/kg bw/day. However, due to some deficiencies in the study (e.g., reduced number of test animals per group), the 90-day oral study with the read across substance, C12-16 ADBAC, has been used for hazard assessment of systemic effects following repeated dosing via dermal route.

However, in line with the Biocides dossier on the read across substance, it can be concluded that there were no primary systemic effects observed in the repeated dose studies and all observed effects could be attributed to local gastrointestinal irritaton/corrosion and consequent reduced food intake. Therefore, the derivation of a DNEL for systemic effects via oral or dermal route has been deemed inappropriate.

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:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

From June 18, 1987 to June 21, 1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

KL2 due to RA

Justification for type of information:

Refer to section 13 for details on the read-across justification. The study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 82-1 (90-Day Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animals
- Source: Sprague-Dawley CD rats were obtained from Charles River Breeding Laboratories, Portage, MI, USA.
- Age at study initiation: 7 weeks
- Weight at study initiation: 221.6-250.9 g (males); 147.7-174.4 g (females)
- Housing: Animals were housed one animal/side of divided stainless steel cages (solid sides with wire mesh floors) mounted in a stainless steel Maxi-Rack (Hazleton Systems, Inc., Aberdeen, MD).
- Diet: Ground Purina Certified Rodent Chow # 5002 (Ralstor Purina Co., St. Louis, MO), ad libitum
- Water: Tap water, ad libitum. Water was provided by an automatic watering system with demand control valves mounted on each cage rack
- Acclimation period: 1 week

Environmental conditions:
- Temperature: 22 ± 3°C
- Humidity: 40-70%
- Photoperiod: 12h light/12h dark

In-life dates: From: 18 June 1987 to: 22 September 1987

Route of administration:

oral: feed

Vehicle:

other: Ground Purina Certified Rodent Chow # 5002

Details on oral exposure:

Diet preparation: Test diets were prepared by direct addition of the test substance to ground rodent feed. A concentrated premix was prepared to ensure maximal loss of the ethanol (approximately 12% by weight) from the test substance during the original mixing time of 1h. Test diets were prepared by appropriate dilutions of the concentrated premix or higher diet concentrations.
- Rate of preparation of diet (frequency): Fresh diet was prepared and offered to the animals each week.
- Mixing appropriate amounts with (Type of food): Ground Purina Certified Rodent Chow # 5002
- Storage temperature of food: Diets were stored in polypropylene containers at room temperature.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Experimental diets were analyzed for stability, homogeneity and concentration of test substance in the diet by using liquid chromatography.
- Homogeneity studies performed on samples from all dietary concentrations indicated that test substance was uniformly distributed in the diet.
- Stability studies were conducted on diets (8000 and 100 ppm) stored at room temperature in closed polypropylene containers and in glass jars. These analyses indicated that the test substance was stable in the diets for at least 21 d under both storage conditions for all dose levels.
- Concentration verification analyses revealed that the test substance concentrations were 90.7 to 111.8% of nominal for all 5 concentrations.

Duration of treatment / exposure:

95 and 96 days for males and females, respectively.

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0, 100, 500, 1000, 4000 or 8000 ppm (equivalent to 0, 6, 31 and 62 mg/kg bw/day (males) and 0, 8, 38 and 77 mg/kg bw/day (females). [Due to mortality in the 4000 and 8000 ppm treatment groups, the corresponding daily intakes could not be calculated.]
Basis: nominal in diet

No. of animals per sex per dose:

15

Control animals:

yes, plain diet

Details on study design:

- Rationale for animal assignment: Animals were assigned to test groups, based on body weight, by a computer generated, weight stratified randomization procedure. Only rats with body weights within ± 20% of the population mean for each sex were used in the study.

Assignment of animals: The animals were assigned into following groups in the study:
- Group 1(Diet control): Plain diet
- Group 2: 100 ppm test substance in diet
- Group 3: 500 ppm test substance in diet
- Group 4: 1000 ppm test substance in diet
- Group 5: 4000 ppm test substance in diet
- Group 5: 8000 ppm test substance in diet

Observations and examinations performed and frequency:

MORTALITY and CLINICAL SIGNS: Yes
- Time schedule: Twice daily

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Animals were observed once a week for detailed clinical observations, and six days a week for overt clinical signs.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight data were collected weekly for all animals.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, food consumption data were collected weekly for all animals.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Ophthalmic examinations were performed prior to treatment and prior to final sacrifice.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Just prior to sacrifice at study termination
- Anaesthetic used for blood collection: Yes (methoxyflurane)
- Animals fasted: Yes, overnight
- How many animals: Blood samples were collected from 10 animals/sex/group (or from the surviving animals in the 4000 ppm group) for haematology analyses.
- Parameters checked: Hemoglobin, hematocrit, erythrocyte count, erythrocyte indices, platelet count, total leukocyte count, differential leukocyte count, reticulocyte count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Just prior to sacrifice at study termination
- Animals fasted: Yes, overnight
- How many animals: Blood samples were collected from 10 animals/sex/group for clinical chemistry
- Parameters checked: AST (SGPT), ALT (SGOT), creatinine, alkaline phosphatase, gamma glutamyl transpeptidase, glucose, urea nitrogen, total protein, albumin, globulin, A/G ratio, total bilirubin, direct bilirubin, indirect bilirubin, calcium, phosphorous, sodium, potassium, chloride

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

SACRIFICE: Animals were anesthetized with methoxyflurane and exsanguinated by severing the brachial vessel.
GROSS PATHOLOGY: Yes, all animals (surviving) were subject to gross necropsy.
HISTOPATHOLOGY: Yes, histopathologic examinations were performed on selected tissues from 10 randomly selected animals/group from the control and 1000 ppm dose groups. The 1000 ppm group was selected for complete examination because it was the highest dose group without significant mortality.
- Tissues collected for histopathology: Gross lesions, brain, eyes, pituitary, salivary gland, heart, aorta, thymic region, thyroid, lungs, adrenals, trachea, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, spinal cord, pancreas, liver, kidneys, urinary bladder, testes, prostate, epididymis, ovaries, uterus, spleen, lymph nodes, sciatic nerves, sternum

Other examinations:

ORGAN WEIGHT: Prior to sacrifice, body weights were obtained to allow expression of relative organ weights. The liver, spleen, kidney, heart, brain, adrenals, testes and ovaries were weighed for all animals.

Statistics:

- Parametric variables were compared between the dose and control groups using Levene’s test for homogeneity of variances, by analysis of variance and by pooled variance t-tests.
- Non-parametric data were analyzed by the Kruskal-Wallis test or by the Wilcoxon rank sum test as modified by Mann-Whitney.
- Frequency data were compared using Fisher’s exact tests.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

All animals in the 8000 ppm group died. For the 4000 ppm group 12/15 males and 11/15 females died or were sacrificed in a moribund condition.

Mortality:

mortality observed, treatment-related

Description (incidence):

Treatment-related clinical findings were restricted to animals from the 4000 and 8000 ppm groups. The observations were of two types, general cachexia and loose faeces. Findings for the surviving animals were similar to those that died.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decrease in body weight was observed for the 4000 and 8000 ppm dose group surviving the first week of the study. A slight but significant decrease was also noticed in the males of the 1000 ppm dose group.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Decrease in food consumption was observed for the 4000 and 8000 ppm dose group surviving the first week of the study. A slight decrease in the food consumption was also noticed in the males of the 1000 ppm dose group.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

No treatment-related finding at any treatment level was observed.

Haematological findings:

no effects observed

Description (incidence and severity):

No treatment related change was observed for males or females from any treatment group (4000 ppm or lower).

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

No treatment related effect up to 1000 ppm. Significant increases in ALT and phosphorus were observed for 3 surviving males of the 4000 ppm group.

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):

No treatment related effect up to 1000 ppm was observed.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

No treatment related effect up to 1000 ppm was observed. Gross lesions related to the treatment were restricted to the animals that died in the 8000 and 4000 ppm group and to a lesser degree in the animals that survived the 4000 ppm group. The findings were fecal staining of perineal area, emaciation, colour changes of the organs, ileus consisting of distended fluid and gas-filled viscera.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histopathologic changes were observed for animals in the 4000 and 8000 ppm dose group and consisted of congestion of various organs or tissues, mucosal cell degeneration of the villus tips of small intestine and cecum, submucosal edema of stomach, splenic contraction and hepatocellular atrophy.

Histopathological findings: neoplastic:

not examined

Key result

Dose descriptor:

NOEL

Effect level:

31 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: the dose of 500 ppm is equivalent to 31 mg/kg bw/day for males and 38 mg/kg bw/day for females

Key result

Dose descriptor:

NOEL

Effect level:

38 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: the dose of 500 ppm is equivalent to 31 mg/kg bw/day for males and 38 mg/kg bw/day for females

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

62 mg/kg bw/day (nominal)

System:

other: GI tract, hepatobiliary and spleen (males)

Organ:

colon

ileum

intestine

liver

spleen

stomach

Treatment related:

yes

Dose response relationship:

yes

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

77 mg/kg bw/day (nominal)

System:

other: GI tract, hepatobiliary and spleen (females)

Organ:

colon

ileum

intestine

liver

spleen

stomach

Treatment related:

yes

Dose response relationship:

yes

Other than a slight trend in reduced body weight and food consumption in males at 1000 ppm, there were no treatment-related findings at 1000 ppm or less. The highest dose of the test substance lead to 100 and 80% mortality for 8000 and 4000 ppm group respectively indicating 1000 ppm to be the maximal tolerated dose. The animals that survived at 4000 ppm were cachectic and debilitated. The probable cause of death was ileus and shock. The females showed less aberrations in all measurements than the males.

Mortality at high doses was considered to occur at concentrations gastrointestinal mucosa and resulting in dehydration and wasting or affects the gastrointestinal flora. The observed effects were all related to the irritation and corrosivity properties of the substance and no specific organ toxicity was evidenced. The NOEL of the study was based on reduction in body weight and body weight gain, consistent with decreased food consumption. Therefore, it was concluded that all effects could be attributed to local gastrointestinal irritaton/corrosion and consequent reduced food intake without observing any primary systemic effect.

Conclusions:

Based on the results of the read across substance study, the NOAEL for the test substance is considered to be 500 ppm in the diet, i.e., equivalent to 31 mg/kg bw/d (i.e. 25 mg a.i./kg bw/d) for males and 38 mg/kg bw/d (i.e. 30 mg a.i./kg bw/d) for females.

Executive summary:

A study was conducted to determine the repeated dose oral toxicity of the read across substance, C12-16 ADBAC (active ingredient: approx. 80%), according to OECD Guideline 408 and US EPA OPP 82 -1, in compliance with GLP. This sub-chronic oral toxicity study (90 d) was realised in Sprague-Dawley rats. The rats were administered daily dietary levels of 0, 100, 500, 1000, 4000 and 8000 ppm test substance, equivalent to 0, 6, 31 and 62 mg/kg bw/d (i.e. 0, 4.8, 25 and 50 mg a.i./kg bw/d) (males) and 0, 8, 38 and 77 mg/kg bw/d (i.e. 0, 6.4, 30 and 62 mg a.i./kg bw/d) (females) for 95 and 96 days, respectively. Daily intakes at 4000 and 8000 ppm could not be calculated due to high mortality. The animals were observed for mortality, clinical signs, body weight, food consumption, hematology and clinical chemistry at termination. Gross and histopathological examinations were also performed. A slight trend in reduction of body weight and food consumption in males at 1000 ppm was observed. Besides this, there were no treatment-related findings at 1000 ppm or lower. There was 80 and 100% mortality at 4000 and 8000 ppm, respectively. Clinical signs of toxicity (general cachexia and loose faeces), decreased food consumption and body weights, gross necropsy findings (including increased amounts of liquids or semi-solid material within the stomach, jejunum, ileum and cecum) were also observed at 4000 and 8000 ppm. The cause of morbidity and death was assumed to be shock secondary to fluid and/or ionic shifts in the gastro-intestinal tract. Under study conditions, the NOAEL for the C12 -16 ADBAC was considered to be 500 ppm in the diet, i.e., equivalent to 31 mg/kg bw/d (i.e. 25 mg a.i./kg bw/d) for males and 38 mg/kg bw/d (i.e. 30 mg a.i./kg bw/d) for females (Van Miller, 1988). Based on the results of the read across substance study, the NOAEL for the test substance, C14 ADBAC, can be considered to be 500 ppm in the diet, i.e., equivalent to 31 mg/kg bw/d (i.e. 25 mg a.i./kg bw/d) for males and 38 mg/kg bw/d (i.e. 30 mg a.i./kg bw/d) for females.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

25 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Guideline compliant study

System:

other: no primary systemic effects observed

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

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:

key study

Study period:

March 06, 1972

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

A study was conducted to determine the short term repeated dose dermal toxicity of the test substance following application of 1 mL/kg bw (i.e., equivalent to 0.8 mg/kg bw/day) and 4 mL/kg bw (i.e., equivalent to 3.2 mg/kg bw/day) of the test solution in rabbits for 20 days.

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

8 oz jar containing a white powder
Lot no.: 263-S
Test substance: Myristyl dimethyl benzyl ammonium chloride
Purity: 99.1%
Dilution of 800 ppm in water was made, based on a 100% active material and used in test

Species:

rabbit

Strain:

not specified

Sex:

male/female

Type of coverage:

occlusive

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: Backs and flanks
- % coverage: 10% of total body area
- Type of wrap if used: Rubberized fabric
- Time intervals for shavings or clipplings: Hair was clipped from their backs and flanks. One half of each test area was abraded as required, while the remainder was left intact

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No washing
- Time after start of exposure: 27 days

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1 mL/kg (0.8 mg/kg bw/day) and 4 mL/kg (3.2 mg/kg bw/day)
- Constant volume or concentration used: Yes

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Dose groups:
1 mL/kg = 0.8 mg/kg bw/day
4 mL/kg = 3.2 mg/kg bw/day

Duration of treatment / exposure:

20 d

Frequency of treatment:

once a day

No. of animals per sex per dose:

1 animal per sex per dose

Control animals:

yes

Observations and examinations performed and frequency:

Food, fluid intake, excretions, behavior and appearance of the animals were observed daily. The animals were weighed, as required. Blood and urine studies were performed at the beginning of the test, at the 20 d interval end prior to autopsy.

Sacrifice and pathology:

At autopsy, gross findings were made and tissues retained for histological examination.

Clinical signs:

not examined

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

Minimal erythema was observed in the treated rabbits on day 5, with minimal edema evident on day 9 in the animals receiving the larger dose. In the same group the erythema became more pronounced on day 11, and persisted with minimal edema at those levels through the rest of the treatment interval. At the lower dose level (1 mL/kg bw) minimal hyperemia showed occasional correction with no edema. On day 15 in the same group hyperemia increased slightly in intensity, but became minimal on day 19 and remained that way to day 21. Minimal edema was observed in the 1 mL/kg bw animals on day 17 through the end of treatment. In the control rabbits minimal hyperemia was observed in the rabbits from day 11 through day 21. All rabbits showed complete recovery of dermal irritation within 4 days after cessation of treatment.

Mortality:

not examined

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Weights increases were normal.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food intake was all within normal parameters at all times.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

Water intake was all within normal parameters at all times.

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

Hematology studies were all within normal parameters at all times.

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Description (incidence and severity):

Urine analysis studies were all within normal parameters at all times.

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

At no time did any of the rabbits manifest abnormal behavior or appearance.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Description (incidence and severity):

Gross findings at autopsy were not significant.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

The histological findings in the treated rabbits were identical to those in the controls.

Histopathological findings: neoplastic:

not examined

Key result

Dose descriptor:

NOAEL

Remarks:

Sysmetic toxicity

Effect level:

ca. 3.2 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

food consumption and compound intake

gross pathology

haematology

histopathology: non-neoplastic

urinalysis

water consumption and compound intake

Key result

Dose descriptor:

LOAEL

Effect level:

ca. 0.8 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

dermal irritation

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

0.8 mg/kg bw/day

System:

integumentary

Organ:

skin

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Table 1: Histopathology results

Rabbit	Dose 800 ppm	Findings
1 F	1 mL/kg	As in control
2 M	1 mL/kg	As in control
3 F	4 mL/kg	As in control
4 M	4 mL/kg	As in control
5 F	4 mL/kg	Water control
6M	4 mL/kg	Water control

Dose groups:

1 mL/kg = 0.8 mg/kg bw/day

4 mL/kg = 3.2 mg/kg bw/day

 

Table 2: Dermal reactions 24 h after each set of applications

Day of treatment		1F	2M	3F	4M	5F*	6M*
2	Erythema	0	0	0	0	0	0
	Edema	0	0	0	0	0	0
3	Erythema	0	0	0	0	0	0
	Edema	0	0	0	0	0	0
4	Erythema	0	0	0	0	0	0
	Edema	0	0	0	0	0	0
5	Erythema	0	0	0	1	0	0
	Edema	0	0	0	0	0	0
6	Erythema	1	0	1	1	0	0
	Edema	0	0	0	0	0	0
7	Erythema	1	0	1	1	0	0
	Edema	0	0	0	0	0	0
8	Erythema	1	1	1	1	0	0
	Edema	0	0	0	0	0	0
9	Erythema	1	1	1	1	0	0
	Edema	0	0	0	1	0	0
10	Erythema	0	1	2	2	0	0
	Edema	0	0	0	1	0	0
11	Erythema	1	1	2	2	1	1
	Edema	0	0	0	1	0	0
12	Erythema	0	0	2	2	1	1
	Edema	0	0	1	1	0	0
13	Erythema	0	0	2	2	1	1
	Edema	0	0	1	1	0	0
14	Erythema	0	0	2	2	0	1
	Edema	0	0	1	1	0	0
15	Erythema	0	0	2	2	0	1
	Edema	0	0	1	1	0	0
16	Erythema	0	0	2	2	0	1
	Edema	0	0	1	1	0	0
17	Erythema	0	0	2	2	0	1
	Edema	0	0	1	1	0	0
18	Erythema	0	0	2	2	0	1
	Edema	0	0	1	1	0	0
19	Erythema	1	1	2	2	0	1
	Edema	1	1	1	1	0	0
20	Erythema	1	1	2	2	1	1
	Edema	1	1	1	1	0	0
21	Erythema	1	1	2	2	1	1
	Edema	1	1	1	1	0	0

Conclusions:

Under study conditions, NOAEL for systemic effects and LOAEL for dermal irritation (local effect) were considered to be 3.2 mg/kg bw/day and 0.8 mg/kg bw/day respectively. 

Executive summary:

A study was conducted to determine the short term repeated dose dermal toxicity of the test substance, C14 ADBAC (Purity 99.1%), according to the procedure described in Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, published by the Association of Food and Drug Officials of the United States. In the study, 1 mL/kg bw (i.e., equivalent to 0.8 mg/kg bw/day) and 4 mL/kg bw (i.e., equivalent to 3.2 mg/kg bw/day) of the 800 PPM solution of the test substance were applied over 10% of the total body surface (Hair clipped back and flank) of the rabbits (one rabbit per sex per dose level) for 20 days. After each application of test substance the torsos of the test animals were wrapped with a rubberized fabric to prevent grooming by the rabbits with possible inhalation or ingestion of test product. Survivors were maintained for two weeks after the last application when all animals were autopsied, as required by the reference. Food, fluid intake, excretions, behaviour and appearance of the animals were observed daily. The animals were weighed, as required. Blood and urine studies were performed at the beginning of the test, at the 20 d interval end prior to autopsy. At autopsy, gross findings were made and tissues retained for histological examination. At no time did any of the rabbits manifest abnormal behaviour or appearance. Food and water intake, excretions, blood and urine studies were all within normal parameters at all times. Weights increases were normal. Minimal erythema was observed in the treated rabbits on day 5, with minimal edema evident on day 9 in the animals receiving the larger dose. In the same group the erythema became more pronounced on day 11, and persisted with minimal edema at those levels through the rest of the treatment interval. At the lower dose level (1 mL/kg bw = 0.8 mg/kg bw/day) minimal hyperemia showed occasional correction with no edema. On Day 15 in the same group hyperemia increased slightly in intensity, but became minimal on Day 19 and remained that way to Day 21. Minimal edema was observed in the 1 mL/kg bw animals on Day 17 through the end of treatment. In the control rabbits minimal hyperemia was observed in the rabbits from day 11 through Day 21. All rabbits showed complete recovery of dermal irritation within 4 d after cessation of treatment. Gross findings at autopsy were not significant. The histological findings in the treated rabbits were identical to those in the controls. Under study conditions, NOAEL for systemic effects and LOAEL for dermal irritation (local effect) were considered to be 3.2 and 0.8 mg/kg bw/day respectively (Luy and Frances, 1972).

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral

A 90 d study was conducted to determine the repeated dose oral toxicity of the read across substance, C12-16 ADBAC (active ingredient: approx. 80%), in Sprague Dawley rats, according to OECD Guideline 408 and US EPA OPP 82 -1, in compliance with GLP. In this study, the rats were administered daily dietary levels of 0, 100, 500, 1000, 4000 and 8000 ppm test substance, equivalent to 0, 6, 31 and 62 mg/kg bw/d (i.e. 0, 4.8, 25 and 50 mg a.i./kg bw/d) (males) and 0, 8, 38 and 77 mg/kg bw/d (i.e. 0, 6.4, 30 and 62 mg a.i./kg bw/d) (females) for 95 and 96 days, respectively. Daily intakes at 4000 and 8000 ppm could not be calculated due to high mortality. The animals were observed for mortality, clinical signs, body weight, food consumption, hematology and clinical chemistry at termination. Gross and histopathological examinations were also performed. Other than a slight trend in reduced body weight and food consumption in males at 1000 ppm, there were no treatment-related findings at 1000 ppm or less. The highest dose of the test substance lead to 100 and 80% mortality for 8000 and 4000 ppm group respectively indicating 1000 ppm to be the maximal tolerated dose. The animals that survived at 4000 ppm were cachectic and debilitated. The probable cause of death was assumed to be shock secondary to fluid and/or ionic shifts in the gastro-intestinal tract, which was attributed to irritation and corrosivity properties of the substance. The females showed less aberrations in all measurements than the males. Based on the decreased food consumption and body weights at 1000 ppm, the NOEL for the test substance was established at 500 ppm in the diet, i.e., equivalent to 31 mg/kg bw/d (i.e. 25 mg a.i./kg bw/d) for males and 38 mg/kg bw/d (i.e. 30 mg a.i./kg bw/d) for females (Van Miller, 1988).

Additional sub-chronic (i.e., 8-week study in dogs, 93 dose range finding study in mice) and chronic dietary studies (i.e., 1-year study in dogs and 2-year study in rats) available with the read across substance, resulted in respective NOELs at 800 ppm in dogs (i.e., 27.4-34.3 mg/kg bw/day or 21.92-27.44 mg a.i./kg bw/day), 500 ppm in mice (i.e., 85-102 mg/kg bw/day or 68-81.6 mg a.i./kg bw/day), 400 ppm in dogs (i.e., 13.1-14.6 mg/kg bw/day or 24.8-30.4 mg a.i./kg bw/day) and 1000 ppm in rats (i.e., NOAEL = 44-57 mg/kg bw/day or 35.2-45.6 mg a.i./kg bw/day). Considering that the effects on which the NOEL derivation could have been based, independently on the species tested, was the reduction in body weight and body weight gain, consistent with decreased food consumption. It was concluded that all effects could be attributed to local gastrointestinal irritaton/corrosion and consequent reduced food intake without observing any primary systemic effect. Therefore, the derivation of a NOAEL for systemic effects was deemed inappropriate (Biocides assessment report, 2015).

Dermal

A study was conducted to determine the short term repeated dose dermal toxicity of the test substance, C14 ADBAC (purity: 99.1%), according to the procedure described in Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, published by the Association of Food and Drug Officials of the United States. In the study, 1 mL/kg bw (i.e., equivalent to 0.8 mg/kg bw/day) and 4 mL/kg bw (i.e., equivalent to 3.2 mg/kg bw/day) of the 800 PPM solution of the test substance were applied over 10% of the total body surface (Hair clipped back and flank) of the rabbits (one rabbit per sex per dose level) for 20 days. After each application of test substance the torsos of the test animals were wrapped with a rubberized fabric to prevent grooming by the rabbits with possible inhalation or ingestion of test product. Survivors were maintained for two weeks after the last application when all animals were autopsied, as required by the reference. Food, fluid intake, excretions, behaviour and appearance of the animals were observed daily. The animals were weighed, as required. Blood and urine studies were performed at the beginning of the test, at the 20 d interval end prior to autopsy. At autopsy, gross findings were made and tissues retained for histological examination. At no time did any of the rabbits manifest abnormal behaviour or appearance. Food and water intake, excretions, blood and urine studies were all within normal parameters at all times. Weights increases were normal. Minimal erythema was observed in the treated rabbits on day 5, with minimal edema evident on day 9 in the animals receiving the larger dose. In the same group the erythema became more pronounced on day 11, and persisted with minimal edema at those levels through the rest of the treatment interval. At the lower dose level (1 mL/kg bw = 0.8 mg/kg bw/day) minimal hyperemia showed occasional correction with no edema. On Day 15 in the same group hyperemia increased slightly in intensity, but became minimal on Day 19 and remained that way to Day 21. Minimal edema was observed in the 1 mL/kg bw animals on Day 17 through the end of treatment. In the control rabbits minimal hyperemia was observed in the rabbits from day 11 through Day 21. All rabbits showed complete recovery of dermal irritation within 4 d after cessation of treatment. Gross findings at autopsy were not significant. The histological findings in the treated rabbits were identical to those in the controls. Under study conditions, NOAEL for systemic effects and LOAEL for dermal irritation (local effect) were considered to be 3.2 and 0.8 mg/kg bw/day respectively (Luy and Frances, 1972).

Justification for classification or non-classification

Based on the observed effects and available NOAELs in 90-day oral study together with other sub-chronic and chronic studies with read across substance, it can be concluded that C14 ADBAC does not require classification for STOT RE according to CLP criteria (Regulation EC 1272/2008).