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Description of key information

OECD 422: NOAEL = 1000 mg/kg bw/day (WIL Research Europe, 2013)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

A combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test of LUGALVAN BPC DRY was conducted in rats by oral gavage according to OECD 422 guideline and GLP (WIL Research Europe, 2013).

 

Rationale for dose levels

Based on the results of the dose range finding study (Project 501951; BASF Project 01R0642/12X355) dose levels for this combined 28-day oral gavage study with reproduction/developmental toxicity screening test were 100, 300 and 1000 mg/kg bw/day.

Study outline

After acclimatization, four groups of ten male and ten female Wistar Han rats were exposed by oral gavage to the test substance at 0, 100, 300 and 1000 mg/kg bw/day.

Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to termination.

Females were exposed for 44-49 days, i.e. during 2 weeks prior to mating, during mating, during postcoitum, and during at least 4 days of lactation.

Evaluated parameters

The following observations and examinations were evaluated: mortality / viability, clinical signs (daily), functional observations and locomotor activity (end of treatment), body weight and food consumption (at least at weekly intervals), clinical pathology (end of treatment), macroscopy at termination, organ weights and histopathology on a selection of tissues, and reproduction/developmental parameters, consisting of mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights and macroscopy). Formulations were analyzed once during the study to assess accuracy, homogeneity and stability.

Results/discussion

Accuracy, homogeneity and stability of formulations were demonstrated by analyses.

Parental results:

No parental toxicity was observed up to the highest dose level tested (1000 mg/kg bw/day).

Reproductive results:

No reproductive toxicity was observed up to the highest dose level tested (1000 mg/kg bw/day).

Developmental results:

No developmental toxicity was observed up to the highest dose level tested (1000 mg/kg bw/day).

Conclusion

Treatment with LUGALVAN BPC dry by oral gavage in male and female Wistar Han rats at dose levels of 100, 300 and 1000 mg/kg bw/day revealed no parental, reproductive or developmental toxicity up to 1000 mg/kg bw/day. Based on these results, a parental, reproduction and developmental No Observed Adverse Effect Level (NOAEL) of at least 1000 mg/kg was derived.

Range-Finder

14-Day dose range finding study for a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental toxicity Screening Test of LUGALVAN BPC DRY in rats by oral gavage (WIL Research Europe, 2013)

Guidelines

No guidelines are applicable as this pilot study was used to select dose levels for the Combined Repeated Dose Toxicity Study with the Developmental/Repro Screening Test of LUGALVAN BPC DRY (85R0642/12X354).

Rationale for dose levels

No clinical signs or deaths were observed after single administration of a 34% aqueous solution of the test compound at the dose level of 2000 mg/kg bw in rats (information provided by the sponsor). Based on this information, the dose levels of 0, 300 and 1000 mg/kg bw/day were selected for the present study.

Study outline

After acclimatization, three groups of four male and four female Wistar Han rats were exposed by oral gavage to the test substance at 300 and 1000 mg/kg bw/day. Animals of the control group received the vehicle, water, alone.

Evaluated parameters

The following parameters were evaluated: mortality / viability, clinical signs, body weights, food consumption, clinical laboratory investigations, macroscopy, and organ weights. Formulations were analyzed once during the study to assess accuracy, homogeneity and stability.

Results

Accuracy, homogeneity and stability of formulations were demonstrated by analyses.

Effects at 1000 mg/kg bw/day consisted of a slight body weight loss on Day 10 of study for the females, reduced urea (both sexes) and inorganic phosphate (females) levels, increased kidneys weight for one male, and decreased spleen weights for all males.

In addition, lower inorganic phosphate concentrations were also noted for females at 300 mg/kg bw/day.

Conclusion

Treatment with LUGALVAN BPC DRY by oral gavage in male and female Wistar Han rats at dose levels of 300 and 1000 mg/kg body weight/day revealed slight effects at 1000 mg/kg body weight/day. Based on the results of this range finding study, dose levels for the Combined Repeated Dose Toxicity Study with the Developmental/Repro Screening Test of LUGALVAN BPC DRY (85R0642/12X354) were: 100, 300 and 1000 mg/kg bw/day. As no clinical signs were observed, clinical observations and functional observational tests for the main study (85R0642/12X354) were conducted at least immediately after dosing.

Justification for classification or non-classification

Based on the available data, the test substance is not classified with regard to repeated dose toxicity according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), respectively.

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