Phosphine

Endpoint summary

Additional information

In vitro data

Phosphine was negative in the Ames test, with and without metabolic activation, using S. typhimurium TA 1538, 1535, 1537, 98, 100 and 102 (Stankowski 1990). In a chromosome aberration study using Chinese hamster ovary cells (San Sebastian 1990) phosphine was negative without metabolic activation; the results with metabolic activation were also negative but the positive control for this group did not cause a significant increase in aberrations and therefore these results cannot be considered reliable.

Animal data

Kligerman et al. (1994ab) did not observe any cytogenetic damage as measured by chromosome aberrations, sister chromatid exchange or micronuclei induction in hematopoietic tissues of mice and rat exposed to PH3 (16 ppm / 22.72 mg/m3 for 6 hours periods and 5 ppm / 7.1 mg/m3 for 9 days period). Furthermore, the peripheral blood lymphocyte was used to quantify cytogenetic damage, theses studies are more comparable to the human in vivo studies.

Barbosa et al. (1994b) reported a slight but statistically significant increase in micronuclei polychromatid erythrocytes in the bone marrow of female mice and in the bi-nucleated splenocytes of male and female mice exposed to 4.5 ppm (6.39 mg/m3) for 13 weeks. The interpretation of these results is ambiguous because the significantly difference between sexes in the control group and an adverse effect (on weight gain) was also observed at this concentration (it was the highest dose). At the same time no statistically significant increase in HPRT mutagenisis was seen in the splenocytes from the treated mice. Nevertheless, when the concentration of PH3 was 5.5 ppm (7.81 ppm) and the exposure was limited to 2 weeks, no statistically significant increases in micronuclei were seen in the peripheral blood polychromatide erythrocyte or in binucleated keratinocytes.

McKeon (1993) found no increase in unscheduled DNA synthesis (ie no increase in nuclear labelling) of rat primary hepatocytes at 2 – 3 hours or 12 – 14 hours after a 6 hour inhalation exposure.

the table below summarizes the animal data:

Reference		Klig, 1994a	Klig, 1994a	Barb, 1994b		McKeon 1993
Exposure		6 hours	9 days	2 weeks	13 weeks	6 hours
highest concentration (ppm)		16 +/-1.15	5	5.5	4.5 +/-0.8	23
Type of study	Species
Micronuclei	mice	negative (bone marrow)	negative (blood lymphocyte)	negative (spleen lymphocyte)	positive at the highest concentration (bone marrow)
		negative (splenocyte)		negative (keratonocyte)	positive at the highest concentration (spleen lymphocyte)
	rat		negative (bone marrow)
Sister Chromatid Exchange	mice	negative (splenocyte)	negative (blood lymphocyte)
	rat		negative (blood lymphocyte)
Chromosome Aberration	mice	negative (splenocyte)	negative (blood lymphocyte)
	rat		negative (blood lymphocyte)
HPRT	mice				negative (spleen lymphocyte)
UDS	rat					negative (hepatocyte)

 

Human data (not epidemiological studies)

Barbosa et al. (1994a) did not associate occupational exposure to PH3 with increased levels of chromosome damage in peripheral blood lymphocytes (micronuclei) and urine mutagenicty of fumigant applicators

Garry et al. (1989) associated occupational exposure to PH3, with increased levels of chromosome damage in peripheral blood lymphocytes of fumigant applicators. However, when the subjects were studied 6 weeks to 3 months after fumigation with PH3 had ceased, there was no difference in the number of chromosome damage between men exposed and control subject. Due the lack of information in the age and conditions of exposure was not clear, the reliability was 3.

Conclusion

The slight but statistically significant increases in micronuclei observed by Barbosa et al. (1994b) may be due to the extended period of exposure that was used in that study compared to Kligerman et al. (1994ab).

The possibility also exists that the positive response seen in the Human studies were actually not due to PH3 but to other confounding factors in the fumigators’ environment.

The most likely explanation for the disparate cytogenetic responses seen after some of the in vivo rodent PH3 exposures, is that PH3 is at best, a weak genotoxicant, that sometimes will induce marginal increases in cytogenitic damage when exposures are near toxic levels. There was no evidence of an increase in DNA synthesis following a single inhalation exposure.

 

Short description of key information:
Negative results were obtained in bacterial and mammalian in vitro cell systems. The most likely explanation for the disparate cytogenetic responses seen after some of the in vivo rodent PH3 exposures is that PH3 is at best, a weak genotoxicant, that sometimes will induce marginal increases in cytogenitic damage when exposures are near toxic levels (Kligerman et al., 1994b). There was no evidence of an increase in DNA synthesis following a single inhalation exposure.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Phosphine is listed on Annex VI to Regulation (EC) No 1272/2008 includes lists of harmonised classification and labelling. No change is proposed for these effects.