A mixture of branched and linear C7-C9 alkyl 3-[3-(2H-benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxyphenyl]propionates

Endpoint summary

Description of key information

Subacute NOAEL (rat): 2 mg/kg bw (Annex V; GLP)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

other: Annex V

GLP compliance:

yes

Limit test:

no

Species:

other: Rat (Tif:RAI)

Route of administration:

oral: unspecified

Vehicle:

other: Distilled water containing 0.5% ‘ CMC' and 0.1 % Tween 80

Details on oral exposure:

Method of administration:
Gavage

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Dosing regime: 7 days/week

No. of animals per sex per dose:

Male: 20 animals at 0 mg/kg bw/day
Male: 20 animals at 2 mg/kg bw/day
Male: 20 animals at 50 mg/kg bw/day
Male: 20 animals at 500 mg/kg bw/day
Female: 20 animals at 0 mg/kg bw/day
Female: 20 animals at 2 mg/kg bw/day
Female: 20 animals at 50 mg/kg bw/day
Female: 20 animals at 500 mg/kg bw/day

Details on results:

Clinical observations:

There were no deaths. Mean body weight was depressed at 500
mg/kg from week 2 for males and in week 4 for females. Food
consumption was similarly depressed. Recovery animals showed
recovery from these effects (Through weeks 5-8).

Laboratory findings:
Mild anaemia, associated with higher reticulocyte counts,
was observed in males at 500 mg/kg. Slightly lower vales for
RBC, HGB, and HCT were observed in males at 50 mg/kg, and in
females at 500 mg/kg.

Slight Hyperglycaemia occurred in both sexes at 500 mg/kg
and 50 mg/kg. Other slight changes included elevated plasma
cholesterol and TGC in females at 500 mg/kg, and decreased
plasma protein in males of the same group. Increased ALP for
both sexes at 500 mg/kg and in males only at 50 mg/kg. ASAT
was increased in males and 2 females at 500 mg/kg.


Effects in organs:
Liver weight was increased in males in all dosed groups,
dose-related, and in females at 500 mg/kg Hepatocyte
hypetrophy was seen in both sexes a! 500 mg/kg and 50
mg/kg. Hepatocyte e necrosis occurred at low incidence in
occasional animals, apparently dose related.

Minimal hypertrophy of the thyroid follicular epithelium
occurred in 2 males in each group a! 500 mg/kg and 50 mg/kg
and in 1 female at 50 mg/kg.

Dose descriptor:

NOAEL

Effect level:

2 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

Dose descriptor:

NOEL

Effect level:

2 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

Critical effects observed:

not specified

Conclusions:

Classified as: Not classified

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

2 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Information from migrated NONS file, as per inquiry number 06-2120047284-59-0000 ,permission to refer granted by ECHA

Repeated dose toxicity: inhalation - systemic effects

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

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The 28 day repeated oral dose toxicity of Chiguard has been evaluated in 2 studies.

In the repeated dose toxicity supporting study (84/449/EEC B.7/GLP), Chiguard 5599 was administered daily to 20 (Tif:TAlf(SPF)) rats/sex/dose in 0.5 % aqueous carboxymethylcellulose with 0.1 Tween 80 via gavage at dose levels of 0, 2, 50, 500 mg/kg bw/day for 28 days. There were biochemical changes noted in the top dose group in both sexes. There were biochemical and haematological changes noted in the mid dose group in both sexes. There was a dose-dependent increase in the absolute and relative liver weights among the females from the high-dose group and among the males from the medium and high dose groups. Macroscopically, there was an enlargement of the liver among 2 out of 5 males from the medium-dose group and among all of the treated animals from the high-dose group.After the follow-up observation period a slight, dose-dependent increase in liver weight was revealed among the males from the medium and high dose groups. Hypertrophy of the hepatic cells was determined among both sexes in the medium and high dose groups; hepatic cell necrosis also occurred dose-dependently. A NOEL value of 2 mg/kg bw/day was derived from the study.

In the repeated dose toxicity key study (Annex V/GLP), Chiguard 5599 was administered daily to 20 (Tif:RAI)) rats/sex/dose in 0.5 % aqueous carboxymethylcellulose with 0.1 Tween 80 via gavage at dose levels of 0, 2, 50, 500 mg/kg bw/day for 28 days.

There were no deaths. Mean body weight was depressed at 500 mg/kg from week 2 for males and in week 4 for females. Food consumption was similarly depressed. Recovery animals showed recovery from these effects (Through weeks 5-8). Mild anaemia, associated with higher reticulocyte counts, was observed in males at 500 mg/kg. Slightly lower values for RBC, HGB and HCT were observed in males at 50 mg/kg, and in females at 500 mg/kg. Slight hyperglycaemia occurred in both sexes at 500 mg/kg and 50 mg/kg. Other slight changes included elevated plasma cholesterol and TGC in females at 500 mg/kg, and decreased plasma protein in males of the same group. Increased ALP for both sexes at 500 mg/kg and in males only at 50 mg/kg. ASAT was increased in males and females at 500 mg/kg. Liver weight was increased in males in all dosed groups, dose-related, and in females at 500 mg/kg. Hepatocyte hypertrophy was seen in both sexes at 500 mg/kg and 50 mg/kg. Hepatocyte necrosis occurred at low incidence in occasional animals, apparently dose related. Minimal hypertrophy of the thyroid follicular epithelium occurred in 2 males in each group at 500 mg/kg and 50 mg/kg and in 1 female at 50 mg/kg. A NOEL value of 2 mg/kg bw/day and a NOAEL value of 2 mg/kg bw/day was derived from the study. The full study report was not available but the harmonised classification in the ECHA C&L inventory (checked 15-07-15) does not indicate that a STOT-RE classification is warranted.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The key study provides a NOAEL value; the supporting study only provides a NOEL value.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
An oral 28-day study is available.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
An oral 28-day study is available.

Justification for classification or non-classification

Based on the available information in the dossier, the substance Chiguard 5599 (CAS No. 127519-17-9) does not need to be classified as specific target organ toxicity (repeated) when considering the criteria outlined in Annex I of 1272/2008/EC.