Hydrocarbons, C18-C22, n-alkanes, n-alkenes

Endpoint summary

Description of key information

From the findings of an OECD 422 study conducted on the source substance, the parental NOAEL

for the test animals was considered to be 100 mg/kg/day; however, findings at 500 and 1000 mg/kg/day

were confined to salivation, and kidney findings which may be reversible and not relevant in man. The neonatal NOEL

was considered to be 500 mg/kg/day. As the parental findings in this study are thought not to be relevant in man,

the parental NOAEL for man could be considered to be 1000 mg/kg/day.

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

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 500 and 1000 mg/kg/day, there was a dose related increase in number of animals with salivation (12/20 animals at 500 mg/kg/day and 21/30 animals at 1000 mg/kg/day). Salivation was generally evident immediately after dosing and up to ca 2 hrs post dose. There were a total of 2 premature decedent females on the study: Animal 64 (500 mg/kg/day) and Animal 71 (1000 mg/kg/day). These deaths were considered incidental for Animal 64 and not positively attributed to treatment for Animal 71.

Mortality:

mortality observed, treatment-related

Description (incidence):

At 500 and 1000 mg/kg/day, there was a dose related increase in number of animals with salivation (12/20 animals at 500 mg/kg/day and 21/30 animals at 1000 mg/kg/day). Salivation was generally evident immediately after dosing and up to ca 2 hrs post dose. There were a total of 2 premature decedent females on the study: Animal 64 (500 mg/kg/day) and Animal 71 (1000 mg/kg/day). These deaths were considered incidental for Animal 64 and not positively attributed to treatment for Animal 71.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

At 500 and 1000 mg/kg/day, occasional salivation noted in some males and females.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Kidney weights statistically higher than Controls in main study males receiving 500 or 1000 mg/kg/day when adjusted for body wt.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

At 500 and 1000 mg/kg/day, microscopic findings were noted in the kidneys (basophilic tubules and hyaline droplets) of the main study males, considered to be treatment related.

Histopathological findings: neoplastic:

not specified

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

Conclusions:

At 1000 mg/kg/day, there was an increase in the number of animals giving birth to dead pups and also in the number losing more than 3 pups over Days 0-4 of lactation, compared with Controls. Therefore, for the neonatal toxicity, the Lowest Observed Adverse Effect Level (LOAEL) was 1000 mg/kg/day and the No Observed Effect Level (NOEL) was considered to be 500 mg/kg/day.
From the findings on this study, the parental NOAEL was considered to be 100 mg/kg/day, however, findings at 500 and 1000 mg/kg/day were confined to salivation, and kidney findings which may be reversible and not relevant in man. The neonatal NOEL was considered to be 500 mg/kg/day.
As findings in this study were considered not to be relevant in man, the parental NOAEL for man could be 1000 mg/kg/day.

Executive summary:

The objective of this study was to assess the toxicity of the source substance in the rat after oral administration. The study was designed to assess possible effects on reproduction and/or development. The males were treated for 2 weeks prior to mating, through to necropsy (ca 4 weeks of treatment). Females were treated for 2 weeks prior to mating, then through mating, gestation and until at least Day 4 of lactation (ca 6 weeks of treatment). Recovery males and females had a 14 day recovery period prior to termination. The recovery animals were necropsied and the organ weight and histopathology data were compared to those of the main study animals.

The animals were monitored daily for any signs of ill health or reaction to treatment. Detailed functional observations were performed weekly, with additional functional observations performed on 5 males and 5 females per group on one occasion; week 4 for males and during early lactation for females.

Blood samples were also taken from 5 males and 5 females per group for laboratory investigations. Males were sampled during week 4 and females were sampled during lactation. In addition, histopathology was conducted on tissues from 5 males and 5 females

from Control and High dose groups.

Treatment with HF-1000 was associated with salivation in animals treated at 500 and 1000 mg/kg/day. The salivation was generally evident immediately after dosing and was evident up to ca 2 hours post dose and may have been due to an unpleasant taste associated with the test item.

The type and distribution of neurotoxicity observations, the haematology parameters and the coagulation and clinical chemistry parameters did not indicate any association with treatment.

At 500 and 1000 mg/kg/day, there was a statistically significant increase in the kidney weights of the main study males, however the kidney weights of the recovery males (1000 mg/kg/day) were similar to those of Controls.

Histopathology findings in the male kidneys (basophilic tubules and hyaline droplets) were noted in main study males treated at 500 and 1000 mg/kg/day. There were associations between increased hyaline droplets in the proximal renal tubules, increased basophilic tubules and the increased kidney weights at these levels. The findings in recovery males were confined to 2/10 with basophilic tubules compared to 1 in Controls.

The hyaline droplets that form in the male rat renal tubules following the administration of materials such as HF-1000 (volatile hydrocarbon) contain alpha-2microglobulin, and are unlikely to occur with hydrocarbon administration in man, as little or none of this protein is present in man, Greaves (2007).

Mating performance and pregnancy performance were similar across the groups.

At 1000 mg/kg/day, there was an increase in the number of animals giving birth to dead pups and also in the number losing more than 3 pups over Days 0-4 of lactation, compared with Controls. Therefore, for the neonatal toxicity, the Lowest Observed Adverse Effect Level (LOAEL) was 1000 mg/kg/day and the No Observed Effect Level (NOEL) was considered to be 500 mg/kg/day.

From the findings on this study, the parental NOAEL was considered to be 100 mg/kg/day, however, findings at 500 and 1000 mg/kg/day were confined to salivation, and kidney findings which may be reversible and not relevant in man. The neonatal NOEL was considered to be 500 mg/kg/day.

As the parental findings in this study are thought not to be relevant in man, the parental NOAEL for man could be considered to be1000 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

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

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Well-conducted study according to established protocol