Bis(3,5-bis(1,1-dimethylethyl)-2-hydroxybenzoato-O1,O2)zinc

Endpoint summary

Description of key information

Subacute NOAEL (rat): 80mg/kg bw (Method B7 of directive 84/449/EEC, OECD 407; 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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD Guideline and GLP compliant study

Qualifier:

according to guideline

Guideline:

other: Directive 84/449/EEC, Method B7

GLP compliance:

yes

Limit test:

no

Species:

other: rat, Wistar albino

Route of administration:

oral: unspecified

Vehicle:

other: no vehicle used

Details on oral exposure:

Method of administration:
Diet administration

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Dosing regime: 7 days/week

No. of animals per sex per dose:

Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 16.1 mg/kg bw/day
Male: 5 animals at 80.4 mg/kg bw/day
Male: 5 animals at 433 mg/kg bw/day

Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 16.9 mg/kg bw/day
Female: 5 animals at 81.7 mg/kg bw/day
Female: 5 animals at 375 mg/kg bw/day

Details on results:

Clinical observations:
Emaciation and rough, dirty coats were observed in group 4: growth , food intake and food efficiency decreased. No other findings.

Laboratory findings:
Haematology:

Group 4: slight increase in red blood cells, haemoglobulin concentration and packed cell volume. Slightly lower total thrombocyte counts.

Clinical biochemistry:
Group 4: Increase in alkaline phosphatase, GOT and GPY activities and in total bilirubin, urea and chloride levels.
Also a decrease in fasting blood glucose level was noted.

Urinalysis:
Group 4 females: a slight dose-related increase in urine production, related to a decrease in urine density.

Effects in organs:
Group 4: decrease in absolute liver weights (male and female) and in several other organs (females only). Relative weights of testes and adrenals were increased (males only)

The relative weight of the liver was slightly increased in males of Group 3 and decreased in females in Group 4.

Pathology:
Group 4: 9/10 animals showed less pronounced lobular pattern compared to the control animals, due to hypertrophy of the centrilobular hepatocytes.

All other findings were commonly seen in the strain of rats used.

Dose descriptor:

NOAEL

Effect level:

ca. 80 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day

Dose descriptor:

NOEL

Effect level:

ca. 80 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

80 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Information from migrated NONS file, as per inquiry number 06-0000021669-59-0000.

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

Oral Route:

The repeated oral dose toxicity of bis(3,5-bis(1,1-dimethylethyl)-2-hydroxybenzoato-O1,O2)zinc (CAS No. 42405-40-3)  has been evaluated in 4 studies.

 

One study was disregarded as it was indicated as following OECD 410/GLP, even though data was presented from an oral acute study.

 

A supporting study with the lowest NOAEL value (60mg/kg bw/day) did not follow any guideline or GLP compliance and was so it was not possible to assess reliability.

Another supporting oral gavage study (OECD 407/GLP) indicated a NOAEL of 240 mg/kg day and NOEL of 15 mg/kg/day with clinical biochemistry (males and females) and haematological (females) changes. Increases in relative liver weights in high dose females were noted but microscopically, there were no treatment-related findings.

 

The study chosen as the key study was conducted in accordance with Method B7 of directive 84/449/EEC (supporting text indicated OECD 407) and GLP. The substance was administered in the diet at 0, 200 ppm, 1000 ppm up to a maximum dose of 5000 ppm (males: 433 mg/kg bw and females: 375 mg/kg bw) in 5 male and 5 female rats for 28 days. Clinical observations at the highest dose group included decreased food intake and growth. Although clinical biochemistry alterations in the high dose group included hepatic and hepatobiliary enzyme level changes (GOT/AST, GPT/ALT, AP) and pathological investigations of the liver post-mortem revealed hypertrophy of hepatocytes, there was no additional histopathological analysis to confirm any toxicologically significant changes due to treatment. NOEL and NOAEL values of 80mg/kg bw were assigned and a NOAEL of 80mg/kg bw will be used as the key value for repeated dose oral toxicity. 

 [U1]This need to be revised.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
OECD Guideline and GLP compliant study

Justification for classification or non-classification

According to the Directive 67/548/EEC, the substance bis(3,5-bis(1,1-dimethylethyl)-2-hydroxybenzoato-O1,O2)zinc (CAS No. 42405-40-3) is not classified for repeated dose toxicity. 

According to the CLP Regulation, the substance bis(3,5-bis(1,1-dimethylethyl)-2-hydroxybenzoato-O1,O2)zinc (CAS No. 42405-40-3)   does not need to be classified for specific target organ toxicity (repeated).