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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Materials and methods well described; results presented adequately in text, tables and figures.
Reason / purpose for cross-reference:
reference to same study

Data source

Reference Type:
Inhalation toxicity of phosphine in the rat: acute, subchronic, and developmental
Newton P.E. et al.
Bibliographic source:
Inhalation Toxicology, 5(2):223-239

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
The phosphine was supplied at 1% in nitrogen. Impurities identified in the phosphine used to generate the 1% phosphine in nitrogen mixture (ppm): nitrogen =0.72, oxygen and argon =0.22, carbon monoxide and dioxide =3.61, arsin <2, total hydrocarbons <0.5, other phosphine <50 and moist =0.6.

Test animals

Fischer 344
Details on test animals or test system and environmental conditions:
Females were at least 9 weeks of age at initiation of mating (186-281g).
Tap water and food were provided ad libitum except during the actual exposures. The animals were maintained on a 12:12 hour light/dark cycle. The environment was maintained at 20-23°C and 40-60% relative humidity to the maximum extent possible.

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure (if applicable):
whole body
Details on exposure:
All exposures were conducted in 10000 liter stainless steel and glass chambers.The chambers were operated dynamically at flow rates of 2000L/min (one complete air change every 12 min) and at a slight negative pressure relative to the surrounding area. Prestudy distribution studies showed the phosphine was evenly distributed throughout the chamber. Temperature, relative humidity and chamber airflow were recorded hourly during the exposures.
For the exposures, the 1% phosphine in nitrogen mixture was delivered to the chambers from the cylinder through a stainless steel regulator equipped with a vent and purge valve. . The metered phosphine flow to each chamber was monitored by a digital mass flowmeter. The animals remained in the chambers for 30 min following each exposure. During this time the chamber was cleaned using room air at the same airflow rate used during the exposure.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Samples for GC determination of the phosphine exposure levels were withdrawn hourly through a septum in a line being flushed with camber air from the breathing zone of the animals. Analyses were performed on a Hewlett-Packard model 5890A GC/NPD. Each day the GC was calibrated before exposure initiation and checked after each series of hourly measurements using certified gas standards.
Details on mating procedure:
To provide mated animals, females were cohoused nightly with males (1:1) of the same strain from an in-house breeding colony. Females were observed each morning for evidence of a vaginal plug and/or microscopic observations of sperm in the vaginal rinse. The day evidence of mating was seen was identified as day zero of gestation.
Duration of treatment / exposure:
Everyday over the days 6-15 gestation interval (10 days)
Frequency of treatment:
6 hours/day
Duration of test:
10 days (days 6-15 gestation interval)
No. of animals per sex per dose:
24 pregnant females per dose
Control animals:
yes, concurrent vehicle


Maternal examinations:
Each animal was given a detailed physical examination on day 0, 6-15, and 20 of gestation. Body weights were recorded over the day 0-6, 6-10, 10-16 ad 16-20 gestation intervals.
Ovaries and uterine content:
On day 20 of gestation, all surviving females were sacrificed by exsanguination under ethyl ether anesthesia. Immediately following sacrifice, the ovaries and uterus were excised intact and weighed. Along with recording the number of corpora lutea an each ovary, the numbers and relative locations of live and dead fetuses, early and late resorptions were recorded for each uterine horn.. If no uterine implants were grossly apparent, the uterus was stained with ammonium sulfide. When foci were visualized following staining, the females were considered pregnant in the calculation of pregnancy rate. However, the number of foci was not included in the calculation of uterine implantation data.
Fetal examinations:
Each fetus was individually identified, weighed, sexed, and examined for external malformations/variations to include observation of palatal defects. Approximately one half of the fetuses in each litter were evaluated for visceral malformations/variations using a picrodissection procedure. The heads of these fetuses were fixed in Bouin's solution and processed for evaluation using a razor blade sectioning technique. The remaining fetuses in each litter were processed for staining of the ossified skeletal structures with alizarin red S. These fetuses where then evaluated for skeletal malformations and ossification variations. Fetal and skeletal evaluation were performed under a dissecting microscope.
Statistical evaluation of equality of means was made by appropriate one-way analysis of variance (ANOVA) technique, followed by a multiple comparison procedure if needed. First Bartlett's test was performed to determine if groups had equal variance. If the variances were equal, parametric procedures were used; if not, nonparametric procedures were used. The parametric procedures were the standard one-way ANOVA using the F distribution to assess significance. If significant differences among the means were indicated, Dunnett's test was used to determine which means were significantly different from the control. If a nonparametric procedure for testing equality of means was needed, the Kruskal-Wallis test was used. If differences were indicated, a summed rank test (Dunn) was used to determine which treatments differ from the control. A statistical test for trend in the dose levels was also performed. In the parametric case, standard regression techniques with a test of trend and lack of fit were used. In the nonparametric case, Jonckheere's test for monotonic trend was used.
Statistical analysis of incidence data was performed using contingency tables. First, a standard χ² analysis was performed to determine if the proportion of incidences differed between the groups tested. In keeping with standard statistical practice, if any one cell had an expected value of less than 5, this step was not reported. Second, each treatment group was compared to the control group using a 2x2 Fischer exact test; the significance level was corrected via the Bonferroni inequality to assure an overall test of the stated significance level. Third, Armitage's test for linear trend in the dosage groups was performed. All ratios were transformed via the arc sine transformation prior to analysis.
The test for equal variance (Bartlett's) was conducted at the 1% two-sided risk level. All other statistical tests were conducted at the 5% and 1%, two-sided risk levels.
Pregnancy rates and resorption/implant ratio were calculated.
Historical control data:
No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
In the 7 ppm exposure group, the first 14 females treated died after 3-10 days of exposure (days 8-15 of gestation). Due to this mortality, this group was terminated. No mortality occurred in the other groups. No adverse effect of treatment at an exposure level to 4.9 ppm was evident from the detailed physical evaluation.
Pregnancy rate for the 0.03, 0.33, 2.8 and 4.9 ppm groups were comparable to control.
No adverse effect of treatment at an exposure level to 4.9 ppm was evident from body weights or weight change data over the gestation period. Food consumption data throughout gestation were not adversely affected by treatment to the 4.9 ppm exposure level.
No adverse effect of treatment up to an exposure level of 4.9 ppm was evident from the maternal gross postmortem examination.
No adverse effect of treatment up to an exposure level of 4.9 ppm was evident from uterine implantation data. There was a statistically
significant increase in the mean number of resorption sites and the mean resorption/implantation ratio in the 0.033-ppm group. However, in the absence of similar observations at the higher concentrations of phosphine, these effects are not considered toxicologically relevant.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
Effect level:
ca. 4.9 ppm (analytical)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
Effect level:
> 4.9 ppm (analytical)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
Effect level:
ca. 7 ppm (analytical)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Mean fetal weights and the ratio of female/male fetuses per group for the phosphine-treated groups were comparable to that of control.
No adverse effect of treatment up to an exposure level of 4.9 ppm was evident from the fetal external, visceral or skeletal evaluations.

Effect levels (fetuses)

Dose descriptor:
Effect level:
> 4.9 ppm (analytical)
Based on:
test mat.
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Maternal toxicity NOAEL (10 days) = 4.9 ppm; LOAEL = 7 ppm - death (9.94 mg/m3)
Fetal toxicity NOAEL = 4.9 ppm (6.96 mg/m3)
Executive summary:

Groups of 24 pregnant F344 rats were exposed to 0, 0.033, 2.8, 4.9, or 7 ppm of phosphine for 6 h/day during days 6-15 of gestation. Fourteen females exposed to 7 ppm died after 3-10 days of exposure.

No maternal deaths were observed at lower concentrations, suggesting a steep concentration response with regard to lethality. Due to excessive the mortality, the remaining animals in the 7 ppm group were terminated.

No adverse treatment-related effects were observed in maternal body weight and feed consumption, maternal physical observations, or uterine implantation. No treatment-related effects were observed during maternal postmortem examinations. No treatment-related effects were observed on mean fetal weights or fetal sex ratio.