Z-85

Endpoint summary

Description of key information

The oral administration of the test material to rats by gavage, at dose levels of 100, 500 and 1000 mg/kg bw/day, did not result in any adverse effects of treatment. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Oral

In a key study performed in accordance with OECD Guideline No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test”, the test item was administered by gavage to three groups, each of twelve male and twelve female Wistar rats, for up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 100, 500 and 1000 mg/kg bw/day. A control group of twelve males and twelve females was dosed with vehicle alone (Arachis oil BP). Two recovery groups, each of five males and five females, were treated with the high dose (1000 mg/kg bw/day) or the vehicle alone for forty-two consecutive days and then maintained without treatment for a further fourteen days. Clinical signs, behavioural assessments, body weight change and food and water consumption were monitored during the study. Extensive functional observations were performed on five selected non-recovery males from each dose group after the completion of the pairing phase, and for five selected parental females from each dose group on Day 4 post partum. Hematology and blood chemistry assessments were performed on five non-recovery males and females per dose group prior to termination. Adult non-recovery males were terminated on Day 43/44, followed by the termination of all females and offspring on Day 5 post partum. Any female which did not produce a pregnancy was terminated on or after Day 25 post coitum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.

Following forty-two days of treatment, recovery group animals were maintained without treatment for a further fourteen days. Hematological and blood chemical assessments were performed on all recovery group animals at the end of the treatment-free period. Recovery animals were killed on Day 57. All animals were then subjected to a gross necropsy and histopathological examinations of selected tissues was performed.

Results

There were no unscheduled deaths.

Treatment at 1000 mg/kg bw/day was associated with increased post-dosing salivation for both sexes from Day 15 onwards, with all animals being affected at some stage of the study. At 500 mg/kg bw/day, isolated incidences of increased post-dosing salivation was observed for animals of either sex towards the end of the treatment period. No such effects were detected in animals of either sex treated with 100 mg/kg bw/day.

There were no treatment related effects detected during the functional assessments.

There were no treatment related effects on body weights throughout the study of either treated sex.

No adverse effects on dietary intake were noted for males during the study or for females during the pre-pairing, gestation or lactation phases of the study, including the recovery phase.

Visual assessment of water bottles did not reveal any significant intergroup differences in water consumption.

Assessment of hematology parameters did not indicate any adverse effect of treatment at 100, 500 or 1000 mg/kg bw/day for either sex.

Males at 1000 mg/kg bw/day showed a statistically significant increase in alanine aminotransferase compared with control. Females at this dosage showed statistically significant increases in alanine aminotransferase, aspartate aminotransferase, creatinine and bile acids compared with control. No statistically significant differences from control were apparent for blood chemistry parameters in either sex at both 100 and 500 mg/kg bw/day.

Neither the type, incidence or distribution of necropsy findings for adult animals indicated any adverse effects of treatment.

For non-recovery males at 500 and 1000 mg/kg bw/day, higher absolute and body weight relative liver weights attained statistical significance when compared with control. No such effects were detected in females treated with 1000 or 500 mg/kg bw/day, animals of either sex treated with 100 mg/kg bw/day or recovery animals following fourteen days without treatment.

A treatment related microscopic abnormality was detected in the liver. Minimal centrilobular hepatocellular hypertrophy was evident in two males treated with 1000 mg/kg bw/day. This was considered to be an adaptive response to the test item and was not considered to represent an adverse effect of treatment. No such effects were detected in females treated with 1000 mg/kg bw/day.

Conclusion

The oral administration of the test material to rats by gavage, at dose levels of 100, 500 and 1000 mg/kg bw/day, did not result in any adverse effects of treatment. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg bw/day.

Inhalation

A 28-day repeat dose study by the inhalation route is scientifically unjustified. The substance is unreactive, insoluble and not inhalable and there is no evidence of dermal absorption.

The substance is a UCVB with the majority of components in the molecular weight range of 509 - 551 gm/mol. The substance is slightly soluble in water (< 2.6E-04 g/L), with a relatively high octanol/water partition coefficient (log Kow > 9.4) and a low vapour pressure (0.012Pa @ 25°C). The substance is a two phase substance, i.e. a solid block associated with a small amount liquid at room temperature and pressure. It is only placed on the market diluted in solvent. 

It is not acutely toxic via the oral route and in a 28-day repeat oral dose study the NOEL was > 1000 mg/kg bw/day.

If this substance was to reach the respiratory tract, the physical chemical properties and its bioavailability, as inferred from the oral toxicity data, indicates that uptake is unlikely to occur.

The potential for inhalation toxicity was not measured. However, the vapour pressure indicates a very low propensity to enter atmospheric air in a respirable form (predicted to be ca. 0.1 ppm under ambient conditions). Thus, respiratory absorption under normal use and handling of this material is expected to be inconsequential.

In the absence of adverse effects at the limit of classification in a 28-day repeat oral dose study further investigations for longer dosing periods are not considered scientifically justified.

Therefore, a 28-day repeat inhalation dose study is considered to be scientifically unjustified.

Dermal

A 28-day repeat dose study by the dermal route is scientifically unjustified. The substance is unreactive, insoluble and a severe eye irritant.

The substance is a UCVB with the majority of components in the molecular weight range of 509 - 551 gm/mol. The substance is slightly soluble in water (< 2.6E-04 g/L), with a relatively high octanol/water partition coefficient (log Kow > 9.4) and a low vapour pressure (0.012Pa @ 25°C). The substance is a two phase substance, i.e. a solid block associated with a small amount liquid at room temperature and pressure. It is only placed on the market diluted in solvent. 

The single-dose dermal application of the test material resulted in no manifestations of systemic toxicity that would suggest systemic absorption through cutaneous barriers. The substance is poorly soluble in water, with the majority of components with MW > 500 and high Log Pow values which indicate a disinclination for absorption.

The substance exhibits no local effects other than severe eye irritation.

It is not acutely toxic via the oral route and in a 28-day repeat oral dose study the NOEL was > 1000 mg/kg bw/day. In the absence of adverse effects at the limit of classification in a 28-day repeat oral dose study further investigations via different routes of exposure are not considered scientifically justified.

Therefore, a 28-day repeat dermal dose study is considered to be scientifically unjustified

Justification for classification or non-classification

There are no observed adverse effects in a 28 -day repeat oral dose study in the rat. There are no adverse systemic effects exhibited in any of the toxicologial studies performed on the substance or a close structural analog. In the absence of effects at or below the classification concentration limit of 1000 mg/kg bw/day, the substance will not be classified for long term effects.