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Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD Guideline 422), the NOAEL for systemic toxicity was 1500 ppm (mean achieved doses of 85 mg/kg bw/day for males, 94 mg/kg bw/day for toxicity phase females, 107 mg/kg bw/day for females during gestation and 177 mg/kg bw/day for females during lactation). The NOAEL of test item for reproductive/developmental effects was also concluded to be 1500 ppm.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
89.5 mg/kg bw/day
Study duration:
subacute
Experimental exposure time per week (hours/week):
168
Species:
rat
Quality of whole database:
GLP study conducted acording to OECD guideline 422 with one dose missing (high dose group was terminated earlier due to welfare reasons).
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

In GLP study conducted according to OECD guideline 414, the No-Observed-Adverse-Effect-Level (NOAEL) for maternal toxicity was concluded to be 35 mg/kg bw/day due to the magnitude of the low bodyweight gain and food consumption at 70 mg/kg bw/day and for embryo-fetal survival and development was concluded to be 70 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
35 mg/kg bw/day
Study duration:
subacute
Experimental exposure time per week (hours/week):
168
Species:
rat
Quality of whole database:
GLP study conducted acording to OECD guideline 414.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In a prenatal developmental toxicity study performed according to OECD Guideline 414 and in compliance with GLP, three groups of 20 female rats received Reaction mass of beta-phellandrene and d-limonene and l-limonene at doses of 10, 35 or 70 mg/kg bw/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted Control group received the vehicle, corn oil at the same volume dose as treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.


Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating, blood samples were taken for thyroid hormone analysis and the gravid uterus weight and thyroid weight were recorded. Microscopic pathology investigations were also undertaken. Ano-genital distance was measured for fetuses and all fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.


Treatment was generally well tolerated with no test item-related unscheduled deaths. Thyroid hormones (T3, T4 and TSH levels) and maternal clinical condition was not affected at any dose level investigated, and there were no test item-related organ weight, macroscopic or microscopic abnormalities detected at scheduled termination on Day 20 after mating. At 70 mg/kg bw/day, low overall mean bodyweight gain over Days 6-20 (79% of Control) was observed which correlated with low food intake from Day 10 of gestation, leading to an overall statistically significantly lower food consumption than Control (84% of Control); adjusted weight gain was also markedly lower than in Controls at this dose level (36% of Control). There was no adverse effect of maternal treatment on the mean numbers of implantations, resorptions, live young, the extent of pre- and post-implantation losses, sex ratio, ano-genital distance or on placental, fetal and litter weights, and there were no major or minor abnormalities or skeletal variants considered related to treatment at any dose level investigated.


 


Based on the results of this study, the No-Observed-Adverse-Effect-Level (NOAEL) for maternal toxicity was concluded to be 35 mg/kg bw/day due to the magnitude of the low bodyweight gain and food consumption at 70 mg/kg bw/day and for embryo-fetal survival and development was concluded to be 70 mg/kg bw/day.

Justification for classification or non-classification

In recent GLP repeated dose toxicity studies (OECD guideline 422), systemic toxicity changes were observed in males and females rats exposed to the registered substance mainly due to a decrease in food consumption because of the lack of palatability of the test item mixed in the diet.


Furthermore, no effects on fertility and post-natal effects due to the lack of food consumption of dams were observed (indirect effect). In this study, the NOAEL for reproductive toxicity was not determinable due to absence of effects at the highest dose tested and the NOAEL for developmental toxicity was conservatively set at 1500 ppm (indirect effect due to lack of palatability of the preparations).


Also, in a GLP study according to OECD guideline 414, there was no adverse effect of maternal treatment on the mean numbers of implantations, resorptions, live young, the extent of pre- and post-implantation losses, sex ratio, ano-genital distance or on placental, fetal and litter weights, and there were no major or minor abnormalities or skeletal variants considered related to treatment at any dose level investigated.


Therefore, the registered substance does not need to be classified for reproductive toxicity according to CLP Regulation (EC) n° 1272/2008.

Additional information

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