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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Under the conditions of the test (OECD 421, GLP), the systemic NOAEL was determined to be ​124 and 144 mg/kg bw for male and females, respectively. The reproduction NOAEL was at least 252 mg/kg bw. The developmental NOAEL was 168 mg/kg bw, but considered a secondary effect.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Additional information

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. For fertility the following parameters were evaluated: mating, fertility, conception indices, precoital time, number of corpora lutea and implantation sites, gestation index and duration, parturation and maternal care. For developmental toxicity the following parameters are evaluated: sex ratio, early postnatal pup development including mortality, clinical signs, body weight and macroscopy. Accuracy, homogeneity and stability of the powder diets were demonstrated by analyses.

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. 

Fertility: No reproduction toxicity was observed up to 4.000 ppm.

Developmental: No direct developmental toxicity was observed up to the highest concentration tested (4.000 ppm). The only effect observed was reduced body weight of male and female pups at 4.000 ppm was on Days 1 (13%) and 4 (16%), achieving a level of statistical significance. Weight gain over Days 1-4 was considered normal (47% for Group 4 compared to 51% for Group 1). Therefore, the reduced body weights of the pups at 4.000 ppm was considered a secondary effect caused by the reduced maternal body weights as body weight gain of the pups over Days 1 to 4 of lactation was unaffected.

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. No reproduction toxicity was observed for treatment up to 4.000 ppm. Developmental toxicity at 4.000 ppm consisted of reduced pup body weights, which was considered a secondary effect. A parental NOAEL of 2.000 ppm was established for males and females (124 and 144 mg/kg bw, respectively). The reproduction NOAEL was at least 4.000 ppm (>252 mg/kg bw) and the developmental NOAEL was 2.000 ppm (based on a secondary effect) (168 mg/kg bw). 

Effects on developmental toxicity

Description of key information

See "toxicity to reproduction part" for more information.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rat

Justification for classification or non-classification

Based on the results of the available Repeated dose and Reproductive toxicity studies the substance does not have to be classified for reproductive toxicity (fertility and developmental toxicity)according to EU CLP (EC 1272/2008 and its amendments).