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Additional toxicological data

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Endpoint:
additional toxicological information
Type of information:
other: review of available experimental toxicity results
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Review based on reliable studies performed according to the respective OECD Guidelines
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2010

Materials and methods

Type of study / information:
The author presents a review of reliable acute, local and genotoxicity testing results for beryllium metal powder generated pursuant to REACH.
Principles of method if other than guideline:
All reported studies were performed, when available, according to the respective OECD guidelines:

Acute oral toxicity: OECD423
Skin irritation: OECD 404
Eye irritation: OECD 405
Skin sensitization: OECD 406
Ames-Test: OECD 471
Mammalian cell gen mutation: OECD 476
Mammalian cell chromosome aberration: OECD 473
Unscheduled DNA repair synthesis: OECD 483
Cell transformation: Commission Regulation (EC) No. 440/2008 B.21
Ion formation under simulated lung conditions: no guideline available

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: solid
Details on test material:
- Name of test material (as cited in study report): beryllium

- Substance type: metal

- Physical state: solid

Results and discussion

Any other information on results incl. tables

For detailed results see tables in the attached document.

Acute oral toxicity:

No mortality occurred during the study. No clinical signs related to the administration of the test item were observed. The body weight evolution of the animals remained normal throughout the study. The macroscopical examination of the animals at the end of the study did not reveal any indication of toxicity (table 1 of attached document).

Skin irritation:

No signs of skin irritation was observed at any time point of the study. All animals survived and showed no signs of toxicity or effects on body weight gain (table 2 of attached document).

Eye irritation

Slight initial chemosis and slight to moderate redness of the conjunctiva were observed in all animals. Redness of the conjunctivae was observed until 72 h after administration, and thus animals were observed again after 7 days, by when the redness had completely resolved in all animals (table 3 of attached document).

Skin sensitization

Animals showed no signs of skin reations after challenge exposure. No mortality occurred during the study. No clinical signs related to the test item were observed. The body weight evolution of the animals remained normal throughout the study (table 4 of attached document).

Ion formation

The solubility of beryllium metal differed significantly from the solubility of beryllium chloride, especially under conditions of neutral pH. The percentage of beryllium ions dissolved from metal was found to be factor 3–40 lower than from beryllium chloride. Dissolution kinetics of beryllium metal and beryllium chloride were found to be too different to conduct the in vitro tests with beryllium chloride. Therefore, the genotoxicity experiments were performed with metal extracts (in 0.9% NaCl for Ames-Test and in culture medium for mammalian cell gene mutation/mammalian cell chromosome aberration/UDS/cell transformation) (table 5 of attached document).

Ames-Test

Beryllium metal was tested negativ with and without metabolic activation in two independent experiments (table 6 of attached document).

Mammalian cell gene mutation

Beryllium metal was found not mutagenic with and without metabolic activation (table 7 of attached document).

Chromosome aberration in mammalian cells

No genotoxic potential was identified for beryllium metal neither in the presence or absence of metabolic activation. A single significant increase in the number of aberrant cells upon long-term treatment without metabolic activation is considered treatment related since no dose-response relation was observed and this effect was not observed in parallel experiments (table 8 of attached document).

Mammalian cell unscheduled DNA repair synthesis (UDS test)

Beryllium metal did not induce DNA repair synthesis in the UDS assay, therefore it is not considered as having damaged the DNA. In addition no cytotoxicity was observed. In pre-damaged cells where 96 % cells were in repair synthesis (addition of 2.23 µg/ml 2 -acetylaminofluorene) an effect on DNA was observed. In a repeat experiment DNA damage was high in all concentrations of

2 -acetylaminofluorene, but no cytotoxicity was observed. In conclusion, no direct effect of beryllium metal extracts was detected (table 9 -11 of attached document).

Cell transformation

All tested concentrations of beryllium metal extract showed increased transformation rates compared to control (table 12 of attached document).

Overview on experimental results with beryllium metal

Study

Species or type

Result

Acute oral toxicity

Rat

LD50 > 2000 mg kg-1 b.w.

Skin irritation

Rabbit

No signs of skin irritation at

any time point.

Eye irritation

Rabbit

Slight initial conjunctival

redness, fully reversible

within 7 days. No effects on

cornea or iris.

Skin sensitization (maximization method)

Guinea Pig

Not sensitizing.

Bacterial gene mutation (Ames-Test)

Salmonella typhimurium/

Escherichia coli

Negative

Mammalian cell gene mutation

V79 cell line (in vitro)

Negative

Mammalian cell chromosome aberration

Human lymphocytes (in vitro)

Negative

Mammalian cell unscheduled DNA repair synthesis (UDS test)

Rat primary hepatocytes (in

vitro)

Negative (beryllium exposure

only); indication of reduced

repair of hepatocytes with

damaged DNA

Cell transformation (SHE assay)

SHE cells (in vitro)

Positive

Applicant's summary and conclusion

Conclusions:
No relevant acute oral toxicity, low local irritating properties and no skin sensitizing properties were found for beryllium metal powder.
The genotoxicity tests conducted in vitro, covering gene mutation, chromosome aberration, DNA repair and its inhibition, did not reveal any genotoxic potential for beryllium metal when extracted under simulated lung conditions. No signs of DNA repair as a measure of direct DNA damage, no gene mutation or clastogenicity were observed. Based on these test results, beryllium metal is not a mutagen, clastogen or DNA damager. Beryllium metal extracts did reduce DNA repair of rat hepatocytes that were severely damaged by external stimulus, while no effects were observed in slight or moderately damaged cells. This finding is in agreement with a publication on a soluble beryllium compound. Due to absence of effects at slight or moderate DNA damage (up to doses leading to 50% of the treated cells initiating DNA repair), relevance to human toxicity is considered rather low because the general, as well as the occupationally exposed, population does not have a high degree of background DNA damage. It is recognized that the in vitro systems used in testing have limitations with respect to quantitative assessment. These test results suggest that even if beryllium is considered to be a carcinogen - based upon the weak associations of the past - it clearly exhibits no non-threshold effects.
Executive summary:

A review of newly conducted experimental studies with beryllium metal powder on acute oral toxicity, local skin and eye effects and genotoxicity performed according to the respective OECD Guidelines is given by Strupp.

The author concludes:

"The toxicity of soluble metal compounds is often different from that of the parent metal. Since no reliable data on acute toxicity, local effects, and mutagenicity of beryllium metal have ever been generated, beryllium metal powder was tested according to the respective Organisation for Economical Co-Operation and Development (OECD) guidelines. Acute oral toxicity of beryllium metal was investigated in rats and local effects on skin and eye in rabbits. Skin-sensitizing properties were investigated in guinea pigs (maximization method). Basic knowledge about systemic bioavailability is important for the design of genotoxicity tests on poorly soluble substances. Therefore, it was necessary to experimentally compare the capacities of beryllium chloride and beryllium metal to form ions under simulated human lung conditions. Solubility of beryllium metal in artificial lung fluid was low, while solubility in artificial lysosomal fluid was moderate. Beryllium chloride dissolution kinetics were largely different, and thus, metal extracts were used in the in vitro genotoxicity tests. Genotoxicity was investigated in vitro in a bacterial reverse mutagenicity assay, a mammalian cell gene mutation assay, a mammalian cell chromosome aberration assay, and an unscheduled DNA synthesis (UDS) assay. In addition, cell transformation was tested in a Syrian hamster embryo cell assay, and potential inhibition of DNA repair was tested by modification of the UDS assay. Beryllium metal was found not to be mutagenic or clastogenic based on the experimental in vitro results. Furthermore, treatment with beryllium metal extracts did not induce DNA repair synthesis, indicative of no DNA-damaging potential of beryllium metal. A cell-transforming potential and a tendency to inhibit DNA repair when the cell is severely damaged by an external stimulus were observed. Beryllium metal was also found not to be a skin or eye irritant, not to be a skin sensitizer, and not to have relevant acute oral toxic properties."