Sulfur

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

In accordance with Section 1.2 of REACH Annex XI, testing does not appear to be scientifically necessary as the weight of evidence indicates no concern for reproductive (fertility) effects from sulfur (conclusions from EFSA evaluations on food additives of sulfur-containing substances and EPA assessments for sulfur oxides and Cosmetic Ingredient Review of Sodium Sulfate) and therefore further testing on vertebrate animals is not warranted.

Sulfur is an inorganic element, which in its various forms (elemental, oxidised and reduced) accounts for about 1.9% of the total weight of the earth. Sulfur-deficient environments are rare in nature with chronic exposure to sulfur being the natural state. It is generally recognised as safe (40 CFR §180.2) by the US EPA and "since it does not give rise to metabolites other than such are well known to be intermediary or end products of mammalian metabolic reactions, the intent of chronic testing requirements do not apply to elemental sulfur and its possible metabolites."

In general, sulfur is an essential element in the metabolism of all living organisms, thus chronic exposure to sulfur is the natural state. More specifically, sulfur is unreactive and insoluble. Systemic effects were absent after subacute and subchronic oral exposure and subacute dermal exposure. Although sulfur can be absorbed both dermally and orally, it is mainly expected to be rapidly excreted. In the main, elemental sulfur is expected to be metabolised by plants rather than animals, with human intake of sulfur usually in the form of sulfur-containing amino acids, as well as sulfates and sulfites that may be present in many foods and beverages. Sulfur is only metabolised by intestinal bacteria; there are indications of absorption of metabolites but which are most likely endogenous to the body (e.g. well known to be intermediary or end products of mammalian metabolic reactions). The expectation that no effects on developmental toxic effects will occur as a consequence of sulfur exposure is supported by the long-standing use of sulfur in topically applied, pharmaceutical formulations and as a pesticide and the absence of developmental toxicity.

The weight of evidence looks at the available data on the forms of sulfur expected to be relevant to man, i.e. oxides of sulfur, sulfates and sulfites.

Data source

Reference

Reference Type:

review article or handbook

Title:

Integrated Science Assessment for Sulfur Oxides – Health Criteria

Author:

United States Environmental Protection Agency

Year:

2017

Bibliographic source:

EPA/600/R-17/451 | December 2017 | www.epa.gov/isa

Materials and methods

Test guideline

Guideline:

other: review of tests by various methods on different sulfur containing substances

GLP compliance:

no

Remarks:

Review article; GLP not applicable

Test material

Test material information

Constituent 1

Reference substance name:

Sulfur

EC Number:

231-722-6

EC Name:

Sulfur

Cas Number:

7704-34-9

Molecular formula:

S

IUPAC Name:

sulfur

Test material form:

solid

Test animals

Species:

mouse

Strain:

CD-1

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Remarks on result:

other: No adverse effects on reproduction parameters expected for sulfur containing compounds

Results (fetuses)

Effect levels (fetuses)

Remarks on result:

other: No adverse effects on reproduction parameters expected for sulfur containing compounds

Overall developmental toxicity

Developmental effects observed:

no

Applicant's summary and conclusion

Executive summary:

The EPA concluded that the overall evidence was inadequate to infer a causal relationship between exposure to SO2 and reproductive and developmental outcomes, and that this was consistent with the conclusion reached in the 2008 ISA for Sulfur Oxides (U.S. EPA, 2008).

The Integrated Science Assessment conducted by EPA looked at both animal toxicological studies and human epidemiology studies, with brief summaries of the animal studies considered given below:

- CD-1 female mice were exposed at concentrations of 83.8 or 170 mg/m3 (wholde body) for gestation days 7-18.  No significant effects on hte number of live pups born/litter were observed, but birth weight was reduced at the top dose.

Original study: Singh J. (1989). Neonatal development altered by maternal sulfur dioxide exposure. Neurotoxicology, 10, 523-527.

- CD-1 male and female mice (10/group/sex) were near-continuously exposed (80% of time) at concetrations of 13.1, 31.4 or 78.6 mg/m3 (whole body) from 9 days prior to mating until gestation day 12-14.  Pups were fostered by unexposed dams at birth and evaluated at 2-18 days of age. Decreased food and water intake was noted for parental animals, but no effects were noted for reproductive parameters (including mating, successful pregnancies, litter sizes, sex ratio, birth weight, postnatal body weight gain, somatic and neurobehavioral development).

Original study: Petruzzi S; Dell’Omo G; Fiore M; Chiarotti F; Bignami G; Alleva E. (1996). Behavioural disturbances in adult CD-1 mice and absence of effects on their offspring upon SO2 exposure. Arch Toxicol, 70, 757-766.