Registration Dossier

Administrative data

Description of key information

Overall, the data for C12-16 ADBAC do not suggest difference in sensitivity between species. The effects seen at 1,500 ppm (before lowering the dose) in the 90-day study with dogs (i.e., 50 mg a.i./kg bw/day), and those reported at 2,000 ppm in a 14-day range finding study with dogs (21.5 mg a.i./kg bw/day and 26.4 mg a.i./kg bw/day in males and females respectively) and 28-day oral toxicity study with dogs (36.70 mg a.i./kg bw/day), indicate that the NOAEL is a borderline value and that the dose-response curve should be quite steep. Effects at immediate higher intakes are confined to lower body weight gain, caused by decreased food intake due to the palatability of the compound. As a conservative approach, the average NOAEL of 47.5 mg a.i./kg bw/day from the 90 day repeated dose study in dogs will be used further in this Chemical Safety Report to derive DNELs for C12-14 ADBAC.

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to the OECD guideline 409 as well as in compliance with GLP.
Qualifier:
according to
Guideline:
OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity in Non-Rodents)
GLP compliance:
yes
Limit test:
no
Species:
dog
Strain:
Beagle
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Continuous
Remarks:
Doses / Concentrations:
0, 500, 1500 and 3000 ppm of test substance in the diet. The mean achieved dosages of active substance, based on food consumption and body weight information were as follows: 0, 8, 25 and 50 mg/kg/d (males); 0, 9, 26 and 45 mg/kg/d (females)
Basis:

No. of animals per sex per dose:
4 males and 4 females per dose group
Control animals:
yes, plain diet
Details on study design:
Post-exposure period: none
Observations and examinations performed and frequency:
Observations included: Clinical signs, mortality, body weight, food consumption, Ophthalmology, haematology, clinical chemistry and urinanalysis.
Sacrifice and pathology:
Pathology of all animals (organ weight, gross pathology) and histopathology on the control and high dose animals.
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
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis 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
Details on results:
From week 8, the concentration of test substance was reduced to 2500 ppm (equivalent to 1250 ppm of active substance) in the high-dose female group, due to low food intake. The mean achieved dosages of active substance, based on food consumption and body weight information were as follows: 0, 8, 25 and 50 mg/kg/d (males); 0, 9, 26 and 45 mg/kg/d (females).
No clinical signs were attributed to treatment with the test substance. No mortality observed. Body weight: No treatment related effects on the body weight gain were attributed to the test substance. A mean body weight loss was noted in females from the high-dose group when given 3000 ppm of test substance. This body weight loss was not dose-related and correlated to the decrease of food consumption recorded among the females of that dose group. When the dosing was reduced to 2500 ppm of test substance, a mean body weight gain, similar to that noted in the control females was recorded. Consequently, this effect was associated with the low appetency of the diet at this dose-level.
Food consumption: In the 500 and 1500 ppm dose group, the food consumption was unaffected in males and females. A markedly lower (-27%) food consumption was noted in females at the high dose group of 3000 ppm. After reduction of the dose-level to 2500 ppm test substance, the food consumption was only slightly lower (-6%). No effects seen at ophthalmoscopic examination, haematology, clinical chemistry and urine analysis.
No treatment-related effects on organ weights were noted. Gross and histopathology showed no findings.
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: No toxicologically significant effect; 1500 ppm (male) and 1250 ppm (female) were corresponding to 50 and 45 mg a.i./kg/d, respectively.
Dose descriptor:
NOAEL
Effect level:
45 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
other: No toxicologically significant effect; 1500 ppm (male) and 1250 ppm (female) were corresponding to 50 and 45 mg a.i./kg/d, respectively.
Dose descriptor:
LOAEL
Effect level:
>= 50 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
Under the condition of the study, the 90-d NOAEL for systemic effects in Beagle dogs was established at the highest tested dose of 1500 or 1250 ppm active substance in males and females, respectively (i.e., corresponding to 50 or 45 mg a.i./kg bw/d, respectively).
Executive summary:

A guideline compliant 90 day dietary study in Beagle dogs was conducted at doses of 0, 500, 1,500 and 3,000 ppm (corresponding to 0, 250, 750 or 1,500 ppm of active substance). Four males and 4 females per dose group were used. From Week 8, the concentration of test substance was reduced to 2,500 ppm (1,250 ppm of active substance) in the high-dose female group, due to low food intake. The mean achieved dosage of active substance, based on food consumption and body weight were 0, 8, 25 and 50 mg/kg bw/day (males); 0, 9, 26 and 45 mg/kg bw/day (females). No treatment-related toxicologically significant effect was observed up to the highest tested dose. A mean body weight loss observed in females from the high-dose group (3,000 ppm) was not dose-related and correlated to the decrease of food consumption recorded among the females of that dose group. When the dosing was reduced to 2,500 ppm of test substance, a mean body weight gain, similar to that noted in the control females was recorded. Consequently, this effect was associated with the reduced palatability of the diet at this dose-level. Under the conditions of the study, the 90-day NOAEL for systemic effects in Beagle dogs was established at the highest tested dose of 1,500 or 1,250 ppm active substance in males and females, respectively (i.e., corresponding to 50 or 45 mg a.i./kg bw/day, respectively) (Guilaumat P-O, 2006).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
47.5 mg/kg bw/day
Study duration:
subchronic
Species:
dog
Quality of whole database:
The information requirement for this tonnage band is sufficiently met with the available data.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The substance is a sticky solid with a low vapour pressure. Due to its physical state and physico-chemical properties, it is unlikely that this substance will form inhalable dust, mist or fumes during normal processing and use conditions. In case inhalable forms of the substance are created under particular conditions (e.g. spraying, elevated temperature/pressure), appropriate risk management measures such as closed systems, exhaust ventilation or wearing of respirators are implemented to control exposure. Under such conditions, the risk to humans following inhalation exposure can be considered minimal and further testing involving vertebrate animals may be omitted, in accordance with Annex XI (1.2) of the REACH regulation.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Oral

A guideline compliant 28 day dietary study in Beagle dogs was conducted with the read-across substance C12-16 ADBAC at dose levels of 0, 500, 1,000 and 2,000 ppm, corresponding to approximately 0, 250, 500 and 1,000 ppm of active test substance, respectively. Two males and 2 females per dose group were used. The homogeneity and stability of the active substance under the administration conditions was checked before treatment start. Concentrations of the active substance were measured in each dietary admixture in Weeks 1 and 4. No treatment-related effects were observed up to the highest tested dose. Under the conditions of the study, the 28 day NOEL for systemic effects in Beagle dogs was established at the highest tested dose of 1,000 ppm (corresponding to a mean actual dose level of 36.70 mg a.i./kg bw/day) (Gaou I, 2006).

A guideline compliant 90 day dietary study in Sprague-Dawley rats was conducted at concentrations of 0, 800, 2000, 5,000 ppm of the read-across substance C12-16 ADBAC (equivalent to 0, 28, 68 and 166 mg a.i./kg bw/day for the males and 0, 30, 74 and 188 mg a.i./kg bw/day for the females). Ten males and 10 females per dose group were used. No signs indicative of toxicity were observed in any group. At 5,000 ppm, the only effect was a decrease in body weight gain (statistically significant) correlating with lower food consumption due to the low palatability of the test substance. Under the conditions of the study, the NOAEL for systemic effects was established at the highest tested dose of 5,000 ppm (equivalent to 166 and 188 mg a.i./kg bw/day for males and females, respectively) (Chevalier G, 2002).

A subchronic oral toxicity study with the read-across substance C12-16 ADBAC was conducted in Sprague-Dawley rats. The rats were administered daily dietary levels 0, 100, 500, 1,000, 4,000, or 8,000 ppm of the test substance equivalent to 0, 6, 31 and 62 mg/kg bw/day (i.e., 0, 4.8, 25 and 50 mg a.i./kg bw/day) (males) and 0, 8, 38 and 77 mg/kg bw/day (i.e., 0, 6.4,30 and 62 mg a.i./kg bw/day) (females) for 95 and 96 days, respectively. Daily intakes at 4,000 and 8,000 ppm could not be calculated due to high mortality. The animals were observed for mortality, clinical signs, body weight, food consumption, hematological and clinical chemistry at termination. Gross examination and histopathological examinations were also performed. A slight trend in reduction of body weight and food consumption in males at 1,000 ppm was observed. Besides this, there were no treatment-related findings at 1,000 ppm or lower. There was 100 and 80% mortality at 8,000 and 4,000 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 4,000 and 8,000 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 the conditions of the test, the NOAEL was considered to be 500 ppm in the diet, equivalent to 31 mg/kg bw/day (i.e., 25 mg a.i./kg bw/day) for males and 38 mg/kg bw/day (i.e., 30 mg a.i./kg bw/day) for females (Van Miller JP and Weaver EV, 1988).

A guideline compliant 90 day dietary study in Beagle dogs was conducted at doses of 0, 500, 1,500 and 3,000 ppm of the read-across substance C12-16 ADBAC (corresponding to 0, 250, 750 or 1,500 ppm of active substance). Four males and 4 females per dose group were used. From Week 8, the concentration of test substance was reduced to 2,500 ppm (1,250 ppm of active substance) in the high-dose female group, due to low food intake. The mean achieved dosage of active substance, based on food consumption and body weight, were 0, 8, 25 and 50 mg a.i./kg bw/day for males and 0, 9, 26 and 45 mg a.i./kg bw/day for females. No treatment-related toxicologically significant effects were observed up to the highest tested dose. A mean body weight loss observed in females from the high-dose group (3,000 ppm) was not dose-related and correlated to the decrease of food consumption recorded among the females of that dose group. When the dosing was reduced to 2,500 ppm of test substance, a mean body weight gain, similar to that noted in the control females, was recorded. Consequently, this effect was associated with the reduced palatability of the diet at this dose-level. Under the conditions of the study, the 90 day NOAEL for systemic effects in Beagle dogs was established at the highest tested dose of 1,500 or 1,250 ppm active substance in males and females, respectively (corresponding to 50 and 45 mg a.i./kg bw/day, respectively) (Guilaumat P-O, 2006).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Most recent and robust study conducted in higher species resulting in lowest NOAEL; OECD guideline and GLP compliant

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The substance is a solid with a low vapour pressure. Due to its physical state and physico-chemical properties, it is unlikely that it will form inhalable dust, mist or fumes when handled and used in solid form. In case inhalable forms of the substance (either pure or in aqueous solutions) are created under particular conditions (e. g. spraying, elevated temperature/pressure), appropriate risk management measures such as closed systems, exhaust ventilation or wearing of respirators are implemented to control exposure. Under such conditions, the risk to humans following inhalation exposure can be considered minimal and further testing involving vertebrate animals may be omitted, in accordance with Annex XI (1.2) of the REACH regulation.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
The substance is a sticky solid with a low vapour pressure. Due to its physical state and physico-chemical properties it is unlikely that this substance will form inhalable dust, mist or fumes during normal processing and use conditions. In case inhalable forms of the substance are created under particular conditions (e.g. spraying, elevated temperature/pressure), appropriate risk management measures such as closed systems, exhaust ventilation or wearing of respirators are implemented to control exposure. Under such conditions, the risk to humans following inhalation exposure can be considered minimal and further testing involving vertebrate animals may be omitted, in accordance with Annex XI (1.2) of the REACH regulation.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Due to the corrosive effect and limited dermal absorption, effects will be characterised by local tissue damage rather than systemic toxicity. Available information on dermal absorption makes route-to-route approach possible. Furthermore, the test substance is classified as corrosive and therefore testing on animals is not scientifically justified for animal welfare reasons.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Due to the corrosive effect and limited dermal absorption, effects will be characterised by local tissue damage rather than systemic toxicity. Available information on dermal absorption makes route-to-route approach possible. Furthermore, the test substance is classified as corrosive and therefore testing on animals is not scientifically justified for animal welfare reasons.

Justification for classification or non-classification

Based on the available NOAELs and LOAELs for the read-across substance C12-16 ADBAC, it can be concluded that C12-14 ADBAC does not require classification according to DSD (67/548/EEC) and CLP (EC 1272/2008) criteria.