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Description of key information

28 day repeated dose oral in rats:  NOEL females = 150 mg/kg day; NOEL males = 15 mg/kg/day (based on hydrocarbon nephropathy, which only occurs in male rats and is not indicatice of a hazard to human health) 
90 day repeated dose oral in rats: NOEL = 300 mg/kg/day
90 day repeated dose inhalation in rats: Based on the irritant effects in group 4, the No-Observed-Adverse-Effect-Level (NOAEL) was considered to be 0.400 mg/L air.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
400 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

28 day repeated dose toxicity oral in the rat: Oral administration of the test material, Benzoic Acid Isononylester, to rats, by gavage, for a period of twenty·eight consecutive days resulted in treatment·related changes in either sex at a dose level of 1000 mg/kg/day and in males treated with 150 mg/kg/day. There was no evidence of treatment related effects in females treated with 150 mg/kg/day or in either sex treated with 15 mg/kg/day for this reason the "No Observed Effect Level" (NOEL) in females was considered to be 150 mg/kg/day and that of males 15 mg/kg/day. The treatment-related changes seen in male rats treated with 150 mglkg/day were confined to renal changes consistent with a well-documented condition known as hydrocarbon nephropathy, which only occurs in male rats and is not indicative of a hazard to human health and a marginal increase in clotting time. These changes are not indicative of a serious adverse health effect as defined by the European Labelling Guide, Commission Directive 2001/59/EC.

90 day repeated dose toxicity oral in the rat: The toxicity of Benzoic Acid Isononylester when given by oral administration (gavage) to rats for 13 consecutive weeks at dosages of 15, 150 and 300 mg/kg/day has been investigated. Following 13 weeks of treatment, no toxicologically relevant changes were observed in body weight, food consumption, clinical observations (reaction to treatment, clinical signs, neurotoxicity assessment, motor activity) and at clinical pathology investigations.The changes in organ weights observed at the post-mortem examinations [increased weights at the high dose level in both sexes (liver and kidney) as well as at the mid-dose level in females (liver), in addition to high dose level males (thymus)], were reversed at the end of the treatment-free period, indicating a complete resolution after sufficient time. However, no corresponding lesion was observed at the histopathology examination.

On the basis of these results, the No Observed Adverse Effect Level (NOAEL) in this study is considered to be 300 mg/kg/day.

Comparing both the 28 day- and the 90 day-study, the LOAEL is at 1000 mg/kg/d. The next highest exposure group originates from the 90 day-study with a NOAEL of 300 mg/kg/d. This value is taken forward for the derivation of the DNEL.

90 day repeated dose toxicity inhalation in the rat: The purpose of this 13-week inhalation study was to assess the cumulative toxicity of Benzoic acid isononylester when administered 5 days per week to rats by inhalation exposure for a period of at least 13 weeks. The results of this study should indicate potential target organs. This study was designed to provide a rational basis for the assessment of the toxicological risk to man. Groups of 10 male and 10 female Wistar rats each were exposed by nose-only flow-past inhalation to target concentrations of 0.100, 0.400 and 5.0 mg Benzoic acid isononylesther/L air in each of groups 2 to 4, respectively. The rats of the control group were exposed to filtered air only. Mortality, clinical signs, body weights, food consumption, functional observation battery, grip strength, landing foot splay, body temperature, locomotor activity, ophthalmoscopic examinations, clinical laboratory investigations, organ weights, macroscopic and microscopic findings were recorded.

Technical Data Exposure to gravimetrically determined aerosol concentrations of 0.100, 0.400 and 4.8 mg Benzoic acid isononylester/L air were achieved in groups 2 to 4, respectively, and were close to the respective targets. The generated aerosols were considered to be respirable to rats and temperature, relative humidity and oxygen concentration during exposure were considered to be suitable for this type of study.

Mortality / Viability All animals survived the scheduled treatment period.

Clinical Signs Treatment-related clinical signs observed during general and detailed observations consisted ofhair loss and scabs at the head region of group 4 animals.

Functional Observational Battery The main findings of the functional observation battery consisted of chromorhinorrhea,hair loss and unkempt fur observed mainly in the animals of group 4.

Grip Strength, Landing Foot Splay and Body Temperature Mean values of grip strength, landing foot splay and body temperature measurements showed no abnormalities when compared to the control group and demonstrate no test item related effect.

Locomotor Activity There was noindication of a test item related effect for thelocomotor activity.

Food Consumption The food consumption was similar across all groups although the lowest mean over treatment values were noted for group 4.

Body Weights Body weight development was mainly reduced in group 4, mainly in males.

Ophthalmoscopic Examinations There were no ophthalmoscopic findings that were considered to be related to the treatment with the test item.

Clinical Laboratory Investigations: Hematology Eosinophil and/or neutrophil counts were increased in males and females of group 4. Clinical Biochemistry Sodium and chloride were dose-dependently increased in males of groups 2 to 4 and in females of group 4. In addition, urea was increased in males and females of group 4 and reduced levels of total cholesterol and phospholipids and increased globulin and total protein levels were noted in males of group 4. Urinalysis In both sexes of group 4, an increase in the relative density along with a decreased volume of urine as well as an increased protein content was measured and aturbid or cloudy appearance of the urine was recorded. Further on, a decreased pH-value in males and elevated ketone concentrations and increased leukocyte counts in females was noted. Organ Weights A treatment-related increase in the organ weights was recorded for the kidneys in males and for the liver in females of group 4.

Macroscopic / Microscopic Findings Skin sores in the nose region were recorded for the animals of group 4. The sores noted at the skin in group 4 animals corresponded histopathologically to chronic inflammation with acanthosis and eschars. Eosinophilic inclusions in the respiratory/olfactory epithelium of the nasal cavity and squamous metaplasia in the larynx was noted mainly in females of group 4. Periportal hepatocellular vacuolation of the liver was noted in a few animals of group 4. An increased incidence and severity of hyaline droplets/granules were noted in the kidneys of male rats of groups 3 and 4. There were no further findings that were considered to be related to treatment with the test item. Accordingly, the skin at the region of the local exposure, the upper respiratory tract (nasal cavity and larynx), the kidneys and the liver were considered as target organs.

Conclusion Based on the irritant effects in group 4, the No-Observed-Adverse-Effect-Level (NOAEL) was considered to be 0.400 mg/L air.

Repeated dose range finder rabbit: A repeated dose range finding study in rabbits revealed a tolerated dose for repeated dose testing of 500 mg/kg/day in rabbits


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Repeated dose toxicity: inhalation - systemic effects (target organ) other: skin

Justification for classification or non-classification

EU classification according to Annex VI of Directive 67/548/EEC: no classification required

GHS classification (GHS UN rev.2, 2007): no classification required

The treatment-related changes seen in male rats treated with 150 mglkg/day in the 28 day repeated dose toxicity study were confined to renal changes consistent with a well-documented condition known as hydrocarbon nephropathy, which only occurs in male rats and is not indicative of a hazard to human health and a marginal increase in clotting time. These changes are not indicative of a serious adverse health effect as defined by the European Labelling Guide, Commission Directive 2001/59/EC. This is supported by the results of a subchronic study (90 day repeated dose toxicity study), where no toxicologically relevant changes were observed in

body weight, food consumption, clinical observations and at clinical pathology investigations. The changes in organ weights observed at the post-mortem examinations were reversed at the end of the treatment-free period, indicating a complete resolution after sufficient time. However, no corresponding lesion was observed at the histopathology examination.