National Toxicology Program

National Toxicology Program

Abstract for TER98002 on Formamide

Developmental Toxicity Evaluation Of Formamide (CAS No. 75-12-7) Administered By Gavage To New Zealand White Rabbits On Gestational Days 6 Through 29

Report Date: March 8, 2001

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.


Formamide is a clear, colorless, and odorless liquid that dissolves a variety of materials, is used in organic synthesis reactions, and is used as an experimental cancer treatment. This study was performed due to the potential for human exposure to FORM and the lack of complete developmental toxicity data.

Dose selection was based on a developmental toxicity screen in New Zealand White rabbits (NTP, 1998c). Naturally-mated female New Zealand White rabbits were dosed by gavage with FORM (10, 20, 40, 80 or 120 mg/kg body weight/day) or its vehicle (deionized/distilled water) on gestational days 6 through 29. Mild maternal toxicity and abortion or early delivery in 3 out of 7 pregnancies were found at 120 mg/kg/day. Although not statistically significant, the reduction in average fetal body weight at the high dose (83% of control weight) was considered to be a biologically relevant response to FORM exposure.

In this study, female NZW rabbits were dosed by gavage with FORM (35, 70, or 140 mg/kg/day) or its vehicle (deionized/distilled water) on gd 6 through 29. The dose volume was 1 ml/kg. The study was conducted in a two-replicate design. Twenty-four timed naturally-mated female rabbits (12 per replicate) were assigned to each group. Does were monitored at regular intervals throughout gestation for clinical signs, food intake, and body weight. At necropsy on gd 30, the following were recorded: maternal clinical condition; body, liver and gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, the numbers of resorbed, dead, or live fetuses were recorded. All live fetuses were weighed, sexed, and examined for morphological anomalies (external, visceral, and skeletal). Approximately one-half of the fetuses were examined for anomalies of the internal head structures.

Abortions or early deliveries were noted in 0, 2, 2, and 8 females in the 0, 35, 70, and 140 mg/kg/day dose groups, respectively. At necropsy, confirmed pregnancy rates were 86-100% per group. One maternal death and four maternal deaths occurred in the low and high dose groups, respectively. Clinical signs associated with FORM exposure were minimal. Reduced or absent fecal output was more often recorded at the high dose (2-13 animals per day), presumably related to reduced feed consumption.

A significant decreasing trend was noted for maternal body weight on gd 15, 18, 21, 24, 27, 29, and 30, maternal body weight change for gd 12 to 15, 15 to 18, 18 to 21 and 21 to 24, but not for weight change during treatment (gd 6 to 29) or gestation (0 to 30). Maternal body weight was significantly depressed in the high dose group on gd 21, 24, and 27. Maternal body weight change was significantly depressed at the high dose for gd 12 to 15, 18 to 21, and 21 to 24. In addition, maternal body weight change was depressed at the mid dose for gd 18 to 21. No significant treatment-related effects were observed for corrected maternal weight gain.

Relative maternal food intake (g/kg/day) exhibited a decreasing trend during most of the treatment period treatment (gd 9 to 24), and was 34-59% of control intake in the high dose group from gd 12 through gd 24. Thereafter, no significant differences were noted among treatment groups for maternal relative feed consumption. Maternal liver weight (absolute and relative to body weight) was equivalent among groups. Gravid uterine weight exhibited a dose-related decreasing trend and was 71% of the control value at the high dose (significant).

FORM exposure decreased average litter size at 140 mg/kg/day that was 66% of the control mean. Mean fetal body weight per litter (males, females, and sexes combined) exhibited a decreasing trend. Mean fetal body weight per litter for males and the sexes combined was significantly decreased at the high dose. There was no effect of treatment on the incidence of external, visceral, or skeletal malformations or variations.

In summary, maternal mortality and other indices of maternal toxicity were noted in this study at the high dose, and the maternal no observed adverse effect level for FORM was 70 mg/kg/day. FORM caused significant treatment-related developmental toxicity at 140 mg/kg/day, consisting of reduced mean live litter size and fetal body weight per litter. Thus, the developmental toxicity NOAEL was also 70 mg/kg/day.

Summary of Maternal and Embryo/Fetal Responses of New Zealand White Rabbits to Formamide Exposure on Gestational Days 6 through 29[a]
Parameter Trend Formamide (mg/kg/day)
35 70 140
Total treated [b]   24 24 24
No. removed[b]   4 2 10
Deaths[b]   1 0 4
Pregnancy rate (%)[b]   100% 91% 90%
Clinical signs of toxicity[c]        
Body weight before treatment (gd 0 or 6) -- -- -- --
Body weight (gd 9, 12, 15, 18, 21, 24, 27, 29, 30)[d] -- --
Body weight change before treatment (gd 3 to 6) -- -- -- --
Body weight change during treatment (gd 6 to 29) -- -- -- --
Body weight change during gestation (gd 0 to 30) -- -- -- --
Body weight change (corrected) -- -- -- --
Relative feed consumption (gd 3 to 6) -- -- -- --
Relative feed consumption (gd 6 to 29)[e] -- -- -- --
No. corpora lutea/dam -- -- -- --
Gravid uterine weight -- --
Liver weight (absolute and relative) -- -- -- --
% Resorptions or fetal deaths/litter -- -- --  
% Litters with resorptions or deaths -- -- -- --
% Litters with 100% prenatal mortality -- -- -- --
No. live fetuses/litter -- --
Average female body weight/litter -- -- --
Average male body weight/litter -- --
% Malformed fetuses/litter
(all, external, visceral, or skeletal)
-- -- -- --
% Litters with malformations
(all, external, visceral, or skeletal)
-- -- -- --
% Fetuses with any variations/litter -- -- -- --
% Litters with any variations -- -- -- --

[a] Trend column-arrow indicates direction of trend. Dose-group column-arrow indicates a significant increase or decrease (p less than 0.05) relative to the control group; -- indicates no significant difference from control (p greater than or equal to 0.05).

[b] Control group values were 24 treated, 2 removed due to a misdirected dose or an injury, 0 dead, and 86% pregnant. At 35 mg/kg/day, two females were removed due to a misdirected gavage dose, two females were removed due to early delivery, and one female was found dead. At 70 mg/kg/day, two females were removed due to early delivery. At 140 mg/kg/day, one female was removed due to a misdirected gavage dose, one female was removed due to an injury, eight females were removed due to abortion or early delivery, and four females were found dead or euthanized moribund.

[c] Pregnant females in the high-dose group had changes in fecal output (reduced or absent amount, 2-13 females/day).

[d] A significant decreasing trend was noted for maternal body weight on gd 15, 18, 21, 24, 27, 29, and 30. Maternal body weight was significantly decreased the 140 mg/kg/day group compared to the control group on gd 21, 24, and 27.

[e] Relative maternal feed consumption was decreased at the high dose on gd 12 to 15, 15 to 18, 18 to 21, and 21 to 24.

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