1-Propanol, 2-methyl-3-[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]-

Endpoint summary

Description of key information

OECD 407: NOAEL was determined to be 150 mg/kg bw/day, based on increased liver weight increases of 33 and 66% in male and female rats, respectively, treated at 1000 mg/kg bw/day.

OECD 421 (male): NOAEL was determined ​to be 124 mg/kg bw, based on increased liver weight increase of 16% in male rats treated at 252-283 mg/kg bw/day.

OECD 421 (female): NOAEL was determined ​to be 144 mg/kg bw, based on lower body weight (6-13%), body weight gain (35-77%) and food consumption (±24%) in female rats treated at 264-395 mg/kg bw/day. 

The overall repeated dose toxicity NOAEL is set to the lowest value of 124 mg/kg bw. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

124 mg/kg bw/day

Study duration:

subacute

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

Information on systemic toxicity is available from a 28-day repeated dose toxicity (OECD TG 407) and from a reproscreen study (OECD TG 421). The NOAELs from both studies are similar 150 mg/kg bw versus 124 mg/kg bw, respectively. 

OECD 407

This study was performed to assess the systemic toxicity of Bornafix to the rat according to OECD TG 407 and following GLP. The substance was administered by oral gavage, once daily, to groups of five male and five female rats for 28 consecutive days at 15, 150 and 1000 mg/kg/day. The test material was prepared as solutions in corn oil at concentrations of 0.3, 3.0 and 20% w/v. A further group of rats (five males and five females ) was held as a concurrent control receiving the vehicle alone. Bodyweights, food consumption and clinical observations were recorded during the study. Blood samples were taken on Day 27 and all animals were killed and examined macroscopically on Day 29. Histopathological examination of the tissues was then initiated.

Results: Clinical signs: There were no treatment-related mortalities. Signs indicative of discomfort following dosing (occasional incidences of paddling of the forepaws and isolated occurrences of lethargy and cage grid biting) were noted among rats treated at 1000 mg/kg/day. Water consumption: Markedly higher than control for female rats treated at 1000 mg/kg/day. Water consumption for males at 1000 mg/kg/day and males and females treated at 150 mg/kg/day was also higher than for controls. Body weight: No toxicological relevant effects on body weight, body weight gain or food consumption were noted during dosing of the substance. Haematology: No toxicological relevant haematology effects were seen in males and females except a slight decrease in total white blood cells in the high dose males (30%) because of lower leucocytes. Biochemistry: Lower glucose levels and higher albumin and globulin (and hence total protein) levels achieved statistical significance in comparison with controls for male rats receiving 1000 mg/kg/day. Other statistically significant differences from control were all within the expected ranges for rats of this age and strain and not considered to be related to treatment. Organ weights: Statistically significantly higher than control relative liver weights were recorded for male (33%) and female (66%) rats treated at 1000 mg/kg/day. Macroscopic pathology: Liver enlargement was seen in most rats receiving 1000 mg/kg/day. Microscopic pathology: Centrilobular or midzonal hepatocyte enlargement in the liver of male and female rats receiving 1000 mg/kg/day. A dose-related degree and incidence of eosinophilic inclusions in proximal tubular epithelium in the kidneys of male rats from all dose groups, which were considered to related alpha-hydrocarbon nephropathy.

Discussion: There was a treatment-related effect in the liver of male and female rats from the high dosage group. Centrilobular or midzonal hepatocyte enlargement, with associated enlarged liver and increased liver weight was recorded. Associated minor biochemical changes (lower glucose, higher protein) were also recorded. This liver finding is and probably related to metabolism of the test substance. The microscopic finding in the kidneys of all treated groups of male rats, a dosage-related incidence of eosinophilic inclusions in proximal tubular epithelium, is characteristic of light  hydrocarbon nephropathy syndrome. This syndrome is specific to male rats and is a common finding with compounds of this nature. This finding, whilst treatment-related, is not considered predictive for a similar effect in man. Additional treatment-related findings for high dosage group rats were occasional signs indicative of discomfort following dosing and an increase in water consumption during Week 3. The higher water consumption, also seen for male and female rats treated at 150 mg/kg/day was thought to be related to the unpalatability of the test substance. Other evidence of unpalatability was seen (e.g. increased salivation following dosing), therefore the increased water consumption was not considered to be  toxicologically important. For rats of the intermediate dosage group, 150 mg/kg/day, the only treatment-related findings were an increase in water consumption, which was not considered toxicologically important, and the light hydrocarbon nephropathy syndrome for male rats which is not considered to be relevant to man. In the low dosage groups, 15 mg/kg/day, the light hydrocarbon nephropathy syndrome in males was the only treatment-related finding.

Conclusion: Based on the effects observed in the liver, the NOAEL was determined to be 150 mg/kg/day.

 

DRF OECD 421

A Dose range finder study was performed to set the dose levels for the main study. Two rats per sex were exposed to 1000, 3000, and 10000 ppm test substance (measured values: 600, 1860 and 7600 ppm) for 14 days. Mortality, clinical signs, body weight and food consumption were observed. In addition, gross pathology was performed and terminal body weight, liver, kidneys, spleen and testes weights were determined at planned necropsy. 

Results: Substance intake: 71 and 68 at 1.000 ppm and 210 and 205 mg/kg bw/day at 3.000 ppm for males and females, respectively. At 10.000 ppm this was 561 mg/kg bw/day for the males. Mortality/clinical signs: At 10.000 ppm, both female animals were killed in extremis on Day 4 of study. These animals showed hunched posture, piloerection, lean appearance, and extremely reduced food consumption. Piloerection was also noted for one male treated at 10.000 ppm on Days 3-4 of study. Body weight: Loss was noted during Days 1-5 of treatment at 10.000 ppm for both males and at 3.000 ppm for both females. This recovered during the remainder of the treatment period. Food consumption: At 10.000 ppm, reduction during the complete treatment period for the males was observed, which was the most severe during the first 3 days. At 3.000 ppm, food consumption was reduced during the first 2 days of study; recovery to normal food consumption levels was noted after that. At necropsy, one female treated at 3.000 ppm showed red-browh discolouration of the thymus. No organ weight changes noted for both sexes.

Conclusion:  In females, ca 561 mg/kg bw/day (7600 ppm) causes the death of both animals. Therefore, dose levels for the main study were selected to be 1.000, 2.000 and 4.000 ppm (75, 150, and 300 mg/kg bw). In addition, as the pelleted diets revealed a very low accuracy (60 to 76%) it was decided to perform the main study with powder diet instead of pellets.

OECD 421

A dietary reproscreen study according to OECD TG 421 was performed following GLP. The dosing was nominally 1000, 2000 and 4000 ppm in the diet to result in 250, 125 and 60 mg/kg bw. Ten males and ten females were exposed per dose level. Males were exposed for 32 days, i.e. 2 weeks prior to mating, during mating, and until termination. Females were exposed for 42-54 days, i.e. during 2 weeks prior to mating, during mating, during postcoitum, and during at least 5 days of lactation. The following repeated dose toxicity parameters were recorded: mortality, clinical signs body weight and food consumption, haematology parameters and organ weights of liver, kidney, testis and epididymides. These organs were also microscopically evaluated.

Results: Dietary analysis showed that the concentrations were within 80 -120% of the nominal. The intake at the highest dose resulted in an intake of 252 -283 mg/kg bw for males and 264 -395 mg/kg bw for females. At the mid dose these results were 124 -139 mg/kg bw and 144 -238 mg/kg bw, respectively. At the low dose these results were 64 - 70 mg/kg bw and 73 -106 mg/kg bw, respectively.

Parental results: Mortality: No mortality occurred during the study period. Clinical signs: Toxicity consisted of the occurrence of piloerection at 4000 ppm. Body weight: In females, at 4000 ppm, body weights was statistically significant reduced during the entire study: 5.3 - 7.0% lower body weight during pre-mating and mating, 5.5 - 13.0% lower body weight during gestation, and 10.8 - 12.1% lower body weight during lactation. A treatment related, statistically significant, reduction in body weight gain was noted during the mating (negative body weight gain), pre-mating (77% lower) and gestation (21 - 35% lower). For males of all dose levels, body weights and body weight gain remained in the same range as controls over the treatment period. Food consumption: In females, at 4000 ppm, post-coitum (mean 23% lower) and lactation (mean 24% lower) food consumption was reduced. Haematology parameters: Similar for all groups male and female. Organ weight: Liver weights were increased for males treated at 2.000 and 4.000 ppm: Absolute 5 and 15% and Relative: 9 and 16%, respectively. Macroscopy: Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment. Microscopy: Hepatocellular hypertrophy was noted at minimal degree in 3/10 males at 4.000 ppm. Microscopic findings in the kidneys consisted of a dose related increase in incidence and severity of hyaline droplets in all treatment groups. Hyaline droplets were considered to represent alpha2μglobulin, a normal protein in male rats which undergoes re-absorption in the proximal cortical tubules. Therefore the presence of hyaline droplets was considered not to be adverse at 1.000 and 2.000 ppm. However, at 4.000 ppm there were associated findings consisting of tubular necrosis, granular cast(s) and tubular basophilia. A range of chemicals are known to increase hyaline droplet formation beyond the physiological capacity of the tubular epithelium which may then result in tubular cell degeneration. These changes are exclusively found in male rats. Therefore, these findings are not predictive for man and their occurrence has no relevance in human safety assessment. 

Conclusion: Treatment with Bornafix by dietary administration in male and female Wistar Han rats at dose levels of 1.000, 2.000 and 4.000 ppm revealed parental toxicity at 4.000 ppm for females and males. A parental NOAEL of 2.000 ppm was established for males and females (124 and 144 mg/kg bw, respectively).

Justification for classification or non-classification

Based on the results of the 28-day repeated oral gavage toxicity study and the Reproscreening study the substance does not have to be classified for repeated dose toxicity according to EU CLP (EC 1272/2008 and its amendments).