Reaction mass of Pentaerythritol bis (2-ethylhexanoate) bis (3,5,5-trimethylhexanoate) and Pentaerythritol tris (2-ethylhexanoate) 3,5,5-trimethylhexanoate and Pentaerythritol 2-ethylhexanoate tris (3,5,5-trimethylhexanoate) and Pentaeryhthritol tetrakis(2-ethylhexanoate) and Pentaerythritol tetrakis (3,5,5-trimethylhexanoate)

Endpoint summary

Description of key information

An oral repeated dose toxicity test (28 days exposure) was performed with the registered substance dosed at 150, 400 and 1000 mg/kg bw/day. It was concluded that this study did not result in a NOAEL (microscopic kidney changes were found in males (not in females) of all dose groups). In a follow-up study, males were dosed for 28 days at 15 mg/kg bw/day. No treatment-related adverse effects were found in this study.

It is of note that ECHA provided study summaries migrated from the SNIF format with limited experimental details.

In the screening study for reproduction and development toxicity (summarized in sections 7.8.1. and 7.8.2), similar results for observed in male rats, whereas no adverse effects wereseen in female rats dosed up to 1000 mg/kg bw/day. Histopathological examination revealed that the effects in kidney were related to accumulation of hyaline droplets, which is non-adverse and not considered relevant effect for humans.

Based on this additional information, it is concluded that the NOAEL for repeated toxicity to be used for human risk assessment is at least 1000 mg/kg bw/day.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data available, ECHA provided study summaries migrated from the SNIF format.

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other: Annex V

GLP compliance:

yes

Limit test:

no

Species:

other: Rat (Sprague-Dawley)

Route of administration:

oral: unspecified

Vehicle:

other: arachis oil B.P.

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: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 400 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 400 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day

Details on results:

Clinical observations:
Mortality data:


There were no deaths during the study.


Clinical observations:


No clinically observable signs of toxicity were detected in
test or control animals throughout the study period.


Bodyweight:


All test animals showed normal gains in bodyweight
throughout the study period, comparable with control.


Food consumption:


There were no adverse effects on food consumption during the
study. Food efficiency in test animals was comparable with
that seen in controls.


Water consumption:


Visual inspection of water bottles revealed no overt
intergroup differences.

Laboratory findings:
Haematology:


There were no treatment-related changes in the
haematological parameters measured.


Blood chemistry:


There were no blood chemical changes which could be
considered toxicologically significant.

A statistically significant increase (30%) in high dose
female inorganic phosphate was detected in comparison with
controls. The change in isolation was considered to be of no
toxicological significance. Statistically significant
increases in low and high dose female aspartate
aminotrasferase (up to 14%) and intermediate and high dose
female alanine aminotransferase (up to 26%) were detected
but no convincing dose relationship was apparent and all
values were within normally accepted ranges.

Effects in organs:
Necropsy:


High dose animals of both sexes showed slight pallor of the
liver at necropsy. Two females showed a more pronounced
pallor and these individuals, plus two males, also showed
accentuated lobular pattern. High dose males also showed
speckled kidneys, however, this macroscopic abnormality was
not apparent in the females from this dose group.

No treatment-related macroscopic changes were detected in
the other dose groups.

Organ weights:


A slight but statistically significant increase (9%) in
relative kidney weight was detected for high dose males in
comparison with controls. All values were within the
normally expected range for rats of this strain and age,
but, in view of the macroscopic and microscopic changes
identified in these animals, the increase was considered to
be toxicologically significant.

No other significant changes were noted.


Histopathology:


Kidneys; Degeneration and necrosis of renal proximal tubules
were observed for male rats dosed at 150, 400 and
1000mg/kg/day. A similar effect was not observed for female
rats.

No other toxicologically significant changes were observed.

Remarks on result:

other: No data available, ECHA provided study summaries migrated from the SNIF format.

Critical effects observed:

not specified

Conclusions:

Classified as: Xn - harmful

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data available, ECHA provided study summaries migrated from the SNIF format.

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other: Annex V

GLP compliance:

yes

Limit test:

yes

Species:

other: Rat (Sprague-Dawley)

Route of administration:

oral: unspecified

Vehicle:

other: arachis oil B.P.

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: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 15 mg/kg bw/day

Details on results:

Clinical observations:
Mortality:


There were no deaths during the study.


Clinical Observations:


No clinically observable signs of toxicity were detected in
test or control animals throughout the study period.


Bodyweight:


No adverse effect on bodyweight development was detected.


Food Consumption:


No adverse effect on dietary intake was detected.


Water Consumption:


No overt intergroup differences were detected.

Laboratory findings:
Haematology:


No overt intergroup differences were detected.


Blood Chemistry:


No treatment-related effects were detected.

Effects in organs:
Organ Weights:


No treatment-related effects were detected. Specifically,
kidney weights were unaffected by treatment with the test
material.


Necropsy:


No treatment-related macroscopic abnormalities were
detected.


Histopathology:


No treatment-related microscopic renal changes were
observed.

Dose descriptor:

NOAEL

Effect level:

15 mg/kg bw/day (nominal)

Basis for effect level:

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

Dose descriptor:

NOEL

Effect level:

15 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: Xn - harmful

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Two studies were used that were found to be reliable under previous evaluation scheme. The potential adversity and the relevance of the results were re-evaluated in light of the screening study for reproduction and developmental toxicity.

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

Justification for classification or non-classification

Based on the current data-set, RB68 is not classified and has no obligatory labelling requirement for repeated dose toxicity toxicity according to Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).