Registration Dossier

Diss Factsheets

Administrative data

Description of key information

NOEL (28d, rat, oral) = 60 mg/kg bw/day (subacute)(OECD 407; GLP compliant)
NOAEL (13 weeks, rat, oral) = 20 mg/kg/day (subchronic)(OECD 408; GLP compliant)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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

Additional information

Repeated dose toxicity: oral

In the 90-day study two male and one female rat of the high dose (200 mg/kg/day) group died during the treatment period. Since necropsy revealed inflammatory lesions of the respiratory tract, an effect that was not observed in surviving animals of the 90-day study or in animals of the 28-day study, the study authors considered these deaths as caused by a misdosing, i.e., accidental test substance administration into the trachea/lung instead of the stomach. This observation is therefore not relevant for classification.

Effects mainly limited to the high dose groups of the 90-day study were

·      General clinical signs (hypersalivation, loud breathing, hunched posture and piloerection) (slight salivation and piloerection were also observed in the 28-day study, but were completely reversible during the two-week recovery period)

·      findings of the functional observation battery were limited to motor activity that was reduced for males but increased for females (no alterations were observed in the 28-day study)

·      body weights showed a statistical significant reduction only at interim time points, but not at study termination, in males (a decrease in body weight of males at 200 mg/kg/day was also found in the 28-day study and was completely reversible during the recovery period)

·      moderately increased neutrophils, red blood cells, haemoglobin and haematocrit in males and females at 200 mg/kg/day, increased monocytes at 200 mg/kg/day and prothrombin time at 60 and 200 mg/kg/day only in males (most of these were also found to be increased in the 28-day study, but all changes were completely reversible during the recovery period)

·      higher urine volume in males and females at 200 mg/kg/day (not evaluated in 28-day study)

·      increased kidney weights in males at 60 and 200 mg/kg/day and in females at 200 mg/kg/day was the only organ weight change considered test-item related and relevant (no significant organ weight changes were observed in the 28-day study)

Blood biochemistry analysis in the 90-day study revealed

·      reduced chloride in males and females at 200 and 60 mg/kg/day (parameter not affected in the 28-day study)

·      reduced potassium in males at 200 and 60 mg/kg/day and in females at 200 mg/kg/day (20% reduction also seen in 28-day study at 200 mg/kg/day)

·      increased urea in males at 200, 60 and 20 mg/kg/day and in females at 200 and 60 mg/kg/day (about 100% increase also seen in 28-day study at 200 mg/kg/day)

·      increased cholesterol and triglycerides in females at 200 and 60 mg/kg/day, but not in males (parameter not affected in the 28-day study)

·      increased creatinine and ALAT in males and females and inorganic phosphorous in males at 200 mg/kg/day (only ALAT increased by about 50% in the 28-day study at 200 mg/kg/day)

All effects observed in the 28-day study were reversible within the two-week recovery phase (recovery phase was not included in the design of the 90-day study).

Microscopic examination in the 90-day study revealed degenerative/regenerative changes in the kidneys of all males and females at 200 mg/kg/day and five males and two females at 60 mg/kg/day.

Observations included

·      increased incidences of renal tubular basophilia (4/20 rats at 60 mg/kg/day and 20/20 at 200 mg/kg/day) with a relevant increase in severity only at 200 mg/kg/day

·      renal tubular dilatation (increased severity in 17/20 rats at 200 mg/kg/day)

·      minimal occurrence of apoptosis (3/20 males at 60 mg/kg/day and 13/20 at 200 mg/kg/day)

·      single cell degeneration/necrosis (8/20 rats at 200 mg/kg/day) and increased mitoses (8/20 rats at 200 mg/kg/day)

No histopathological alterations of the kidneys were observed in the 28-day study at any of the dose levels up to 200 mg/kg/day.

Other histopathological findings in the 90-day study were limited to the thymus and spleen of high dose group animals.

Repeated dose toxicity: inhalation

According to the Regulation (EC) 1907/2006 testing on long term inhalation toxicity is considered not being scientifically justified. Since SymWhite 377 is corrosive to rabbit skin, local effects in lungs cannot be completely ruled out. Therefore, and since relevant DNELs for long term inhalation toxicity could be derived by route-to-route extrapolation from a 13 -week oral toxicity study in rats with SymWhite 377, long term testing on inhalation is not considered to be required.

Repeated dose toxicity: dermal

According to regulation (EC) 1907/2006 Annex XI (scientifically unjustified), testing for subacute dermal toxicity is not considered to be required, for the following reason:

 

- Due to the high water solubility (>3 g/L) and a logPow of 2.11, quantitatively relevant dermal adsorption can not be completely ruled out based on theoretical considerations only. However, the lack of toxicity in the acute dermal toxicity study up to a concentration of 2000 mg/kg bw in comparison to the acute oral toxicity (LD50 300-2000 mg/kg bw) may be seen as an indication that this is not a preferential route of entry into the body.

 

- Furthermore, and in accordance with ECHA guidance on information requirements and chemical safety assessment-chapter R.8: characterisation of dose [concentration]-response for human health, May 2008, a DNEL for systemic effects could be derived by route-to-route extrapolation from a 13 -weeks oral toxicity study in rats with SymWhite 377.


Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

Repeated dose toxicity, oral

Reference Davies (2009) is considered as the key study for repeated dose oral toxicity and will be used for classification. The NOAEL was determined to be 20 mg/kg/day in a 13 -week repeated dose toxicity study. The target organ was established to be the kidney.

Specific target organ toxicant (STOT)- repeated exposure: oral

The guidance values for classification as R48 (DSD) and STOT-RE Cat. 2 (CLP) are ≤50 mg/kg bw/d (DSD) and ≤100 mg/kg bw/d (CLP).

 

The small changes in biochemical parameters at 60 mg/kg/day in the 90-day study do not warrant a classification. To conclude on the potential effects at the CLP classification threshold level of 100 mg/kg/day, which was not among the dose levels tested, it is taken into account that all effects that were also observed in the 28-day study at 200 mg/kg/day were completely reversible in the two-week recovery phase and that most effects observed at 200 mg/kg/day had no histopathological correlate, e.g. in the liver. Therefore, these effects do not fulfil the classification criteria.

 

The histopathological effects observed on the kidney at 60 and 200 mg/kg/day in the 90-day study are not considered to fulfil the classification criteria because no histopathological changes were observed in the 28-day study at the same dose levels, and the minimal occurrence of single cell apoptosis and necrosis with concomitant evidence of tissue repair, as evidenced by increased mitotic activity, and is not considered to provide evidence of appreciable cell death, and these mild histopathological changes did not cause significant functional organ changes.

 

Likewise, the other effects observed only at 200 mg/kg/day in the 90-day study were either not observed at the same dose level or completely reversible in the 28-day study, were not considered severe, had no histopathological correlate and overall were not considered to fulfil the CLP classification criteria.

 

In conclusion, the test substance should not be classified for toxicity after repeated administration according to the criteria of the EU Dangerous Substances Directive (67/548/EEC) and the EU Classification Labelling and Packaging Regulation (1272/2008/EEC).

Repeated dose toxicity: inhalation, dermal

No C&L needed.

Categories Display