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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
data waiving: supporting information
Reference

The vapour pressure was determined based on a study conducted with read across substance, C12 -16 ADBAC, using the isothermal thermo gravimetric effusion method according to OECD Guideline 104, EU Method A.4 and EPA OPPTS 830.7950 (Brekelmans, 2012). 


 

Vapour pressure:
0.006 Pa
at the temperature of:
25 °C
Reason / purpose for cross-reference:
data waiving: supporting information
Reference

The appearance, physical state and colour were determined based on a study conducted with read across substance, C12 -16 ADBAC according to EPA OPPTS 830.6302, .6303 and .6304 (Schulze, 2007)

Physical state at 20°C and 1013 hPa:
solid
Form:
solid: crystalline
Colour:
white
Colour intensity:
light

Crystalline, hygroscopic, sticky white solid with a faint marzipan-like odour

Reason / purpose for cross-reference:
data waiving: supporting information
Reference

Based on the results of the read across studies with C12-16 ADBAC, no toxicologically significant systemic toxicity is expected for the test substance. In line with the biocides assessment report, it was concluded that all effects could be attributed to local gastrointestinal irritation/corrosion and consequently reduced food intake without observing any primary systemic effect. Therefore, the derivation of a systemic NOAEL or DNEL was deemed inappropriate

Toxic effect type:
concentration-driven
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
45 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.

System:
other: no true systemic effects
Endpoint conclusion:
no study available
Endpoint conclusion:
no study available
Endpoint conclusion:
no study available
Endpoint conclusion:
no study available

 Oral: 

Study 1: 

Dose range-finding:A 14-day range-finding study was conducted to determine the dose levels for a 90-day repeated dose oral toxicity of the read across substance, C12-16 ADBAC (48.9% active) in Sprague-Dawley rats, according to OECD Guideline 407, in compliance with GLP. In this study, the read across substance was administered to six rats per sex per group at dietary doses of 0, 1250, 2500 and 5000 ppm i.e., equivalent to 0, 650, 1250 and 2500 ppm a.i. or 0, 112, 229 or 436 mg/kg bw/d for males and 0, 116, 229 or 427 mg/kg bw/d for females. Besides lower food intake with related lower increase of body weight gain in all groups, which was due to the palatability of the read across substance, no toxic effects were observed. Under the study conditions, the NOAEL for systemic toxicity was > 2500 ppm (i.e., equivalent to 436 and 427 mg/kg bw/day or 218 and 214 mg a.i./kg bw/d for males and females, respectively) (Chevalier, 2002).  

Main study:A 90-day study was conducted to determine the repeated dose oral toxicity of the read across substance, C12-16 ADBAC (48.9% active in water) in Sprague-Dawley rats according to OECD Guideline 409, in compliance with GLP. In this study, the read across substance was administered to ten rats per sex per group, at dietary doses of 0, 400, 1000 and 2500 ppm (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, based on food consumption and body weight information). No signs indicative of toxicity was observed in any group. At 2500 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 read across substance. Further, some statistically significant deviation from control in haematological and clinical-chemistry values were observed. However, in the absence of a dose-response relation, these effects were considered to be of no clinical significance. Under the conditions of the study, the rat NOEL for systemic effects was established at 1000 ppm (i.e., equivalent to 68 and 74 mg a.i./kg bw/day for males and females, respectively) (Chevalier, 2002).  

 Study 2: 

 A 90 d study was conducted to determine the repeated dose oral toxicity of the read across substance, C12-16 ADBAC (79.7 -80.5% active) 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 read across 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 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 read across 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 read across substance was established at 500 ppm in the diet, i.e., 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, 1988). 

Study 3: 

Dose range-finding:A 14-day range finding study was conducted to determine the dose levels for a 28-day repeated dose oral toxicity of the read across substance, C12 -16 ADBAC (purity 49.9%) in Beagle dogs, according to OECD Guideline 407. In Phase I, four incremental doses of 500, 1000, 2000 and 5000 ppm were administered to 4 animals (2 males and 2 females). At 500 and 1000 ppm, no overt signs of toxicity were noted. At 2000 ppm, a moderate to marked decrease in body weight and food consumption was seen in the male. At 5000 ppm, a slight to moderate decrease in body weight and food consumption was observed in the male and female. No treatment-related laboratory or histopathological changes were noted. Taking into consideration these findings, one male and one female were then treated daily with the read across substance at 2000 ppm (i.e., equivalent to 43 and 53 mg/kg bw/day (21.5 and 26.4 mg a.i./kg bw/day) in males and females respectively) for 2 weeks (Phase II). Under the study conditions, reduced food consumption was recorded throughout the treatment period. A slight decrease in protein, albumin and triglyceride levels and alkaline phosphatase activity was noted as well. Consequently, the dose levels of 250, 500 and 1000 ppm of active read across substance were chosen for the 28-day repeated dose toxicity study in beagle dogs (Gaou, 2004).  

Main study:A 28-day study was conducted to determine the repeated dose oral toxicity of the read across substance, C12 -16 ADBAC (purity 49.9%) in Beagle dogs, according to OECD Guideline 409, in compliance with GLP. In this study, the read across substance was administered to 2 dogs per sex per group, at dietary doses of 0, 500, 1000 and 2000 ppm, corresponding to approximately 0, 250, 500 and 1000 ppm a.i., respectively. The homogeneity and stability of the read across substance under the administration conditions was checked before treatment start. Concentrations were measured in each dietary admixture in Week 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 1000 ppm a.i. (i.e., equivalent to a mean actual dose of 36.70 mg a.i./kg bw/day) (Gaou, 2006).   

Study 4:A 90-day study was conducted to determine the repeated dose oral toxicity of the read across substance, C12-16 ADBAC (49.6% active in water) in Beagle dogs according to OECD Guideline 409, in compliance with GLP. The read across substance was administered to four animals per sex per dose group at dietary doses of 0, 500, 1500 and 3000 ppm (i.e., equivalent to 0, 250, 750 or 1500 ppm a.i.). From Week 8, the concentration of read across substance was reduced to 2500 ppm (i.e., 1250 ppm a.i.) in the high dose female group due to low food intake and reduced body weight among these animals (up to 20%). 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. One out of 4 female dogs in the high dose group (1500 ppm a.i.) showed emaciated appearance and soft faeces. No other clinical signs were attributed to treatment with the read across substance.Themean body weight gain were recorded to be similar to the control females following reduction of the high dose group to 1250 ppm a.i. Consequently, the prior effects on body weights at 1500 ppm a.i. were considered to be due to reduced palatability. Also, slightly lower clinical chemistry parameters (i.e., mean protein and cholesterol levels) were noted in females from the high-dose group when given 1500 ppm a.i., consistently with the decrease of food intake. These differences were no longer observed at the end of the treatment period and after dose reduction to 1250 ppm a.i. Under the study conditions, the 90-d NOAEL for systemic effects in Beagle dogs was established at the highest adjusted test dose of 1250 ppm (i.e., equivalent 45 mg a.i./kg bw/day, respectively) (Guillaumat, 2006).  

Chronic toxicity studies: 

Study 1:A study was conducted to determine the repeated dose oral toxicity study of the read across substance, C12 -16 ADBAC (49.2 - 49.9% active in water) according to OECD Guideline 453, in compliance with GLP. This experiment evaluated the chronic toxicity and carcinogenic potential of the test substance in a combined study. The read across substance was administered daily to Sprague-Dawley rats by dietary admixture at the concentrations of 1000, 2000 and 4000 ppm (equivalent to 500, 1000 and 2000 ppm a.i.) for 52 weeks (toxicology sub-group) (equivalent to 28, 56 or 109 mg a.i./kg bw/d for males and to 33, 65 or 133 mg a.i./kg bw/d for females, respectively) and for 104 weeks (carcinogenicity sub-group) (corresponding to 24, 48 or 97 mg a.i./kg bw/d for males and 29, 58 or 119 mg a.i./kg bw/d for females). The read across substance did not induce any treatment-related mortality or clinical signs when administered daily for 52 or 104 weeks. At 4000 ppm, the mean body weight and body weight gain of the males of the toxicology sub-group and of the males and females of the carcinogenicity sub-group were lower than that of the controls, correlating with slightly lower mean food consumption. There were no significant differences in haematological, biochemical and/or urinalysis parameters at any dose-level for animals of either sub-group, compared with controls. There were no macroscopic or microscopic findings attributable to the read across substance at any dose levels. Under the study conditions, due to the observed lower body weight gain at 4000 ppm substance (significant only in males of 52-week chronic study part; significant in males and females in 104-week carcinogenicity group), the NOEL was established at 2000 ppm (equivalent to 56 and 65 mg a.i./kg bw/d for males and females for chronic groups or 48 and 58 mg a.i./kg bw/d in males and females for carcinogenicity groups) (Appelqvist, 2007).

Study 2:A study was conducted to determine the repeated dose oral toxicity of the read across substance (81.09% in aqueous/ethanol solution) according to OECD Guideline 453 and US EPA OPPTS 870.4300, in compliance with GLP. This two-year combined dietary toxicity and carcinogenicity study was conducted in Sprague-Dawley CD rats. The read across substance was administered rats (60/sex/group) at dose levels of 0, 300, 1000 or 2000 ppm read across substance (equivalent to mean intake levels of 0, 13, 44, and 88 mg/kg bw/d in males and 0, 17, 57 and 116 mg/kg bw/d in females) in the diet daily for 104 weeks. There were two control groups of 60/sex/group each. The animals were observed twice daily and body weights and clinical findings were recorded periodically. Clinical pathology measurements (haematology, clinical chemistry and urinalysis) were made at 6, 12, 18 and 24 months. At termination, a thorough post-mortem examination was conducted on all animals. Histopathology was conducted on a full set of tissues and organs from all animals in the control and high dose groups as well as on selected organs from animals in the low and mid-dose groups. An increased incidence of loose faeces in male rats was observed which was considered to be potentially treatment-related, however, was not of biological significance. A reduction in mean absolute bodyweights and food consumption was observed in males and females in the high dose group. No other treatment related effects were observed for clinical pathology, organ weights, gross and histopathology or ophthalmology. Based on the results of the study, the NOAEL for chronic toxicity was determined to be 1000 ppm in diet (44 mg/kg bw/d for males and 57 mg/kg bw/d for females, equivalent to 35.64 and 46.17 mg a.i./kg bw/d respectively) (Gill, 1991).  

As per the Biocides assessment report on C12-16 ADBAC, which was published by the Italian authorities in June 2015, reported the above studies and stated 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 (US ISC; EQC). 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.” 

Therefore, in line with the biocides assessment report and given that the read across to C12-16 ADBAC can be justified for the test substance based on a category approach, derivation of systemic NOAEL and DNEL has been considered to be non-relevant and only a qualitative local risk assessment has been conducted for the test substance.   

Inhalation: 

The substance has a low vapour pressure (VP = 0.0058 Pa at 25°C, based on read across), which is below the cut-off of 0.01 Pa set for defining low volatility substances, as per the ECHA Guidance R.7a. Therefore, due to its solid physical state and low VP, the test substance 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 (due to corrosive nature of the test substance) 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. Nevertheless, a qualitative risk assessment has been carried out for this route, due to the corrosive nature of the test substance and the fact that the available repeated dose oral studies with the read across substance did not show any primary systemic effects; all observed effects were attributed to local gastrointestinal irritation/corrosion and consequently reduced food intake.  

Dermal:  

A repeated dose dermal toxicity study for the test substance is not required because the endpoint can be assessed based on the available sub-chronic oral studies with the read across substance, which indicated that the main critical effects were due to the corrosive properties of the substance. Further, given the corrosive nature of the test substance together with the fact that the toxicokinetic assessment did not indicate higher absorption potential for the dermal route, any further testing on animals may be omitted due to animal welfare reasons, in accordance with Annex XI (1.2) of the REACH regulation. Nevertheless, a qualitative risk assessment has been carried out for this route, due to the corrosive nature of the test substance. 

Based on the results from the read across oral repeated dose toxicity studies, the test substance does not warrant classification for STOT RE according to the EU CLP criteria (Regulation 1272/2008/EC).  

Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
medium hazard (no threshold derived)
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Hazard assessment conclusion:
medium hazard (no threshold derived)

Data source

Materials and methods

Results and discussion

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion